Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors

ABSTRACT

The invention relates to inhibitors of USP7 inhibitors useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formula: 
     
       
         
         
             
             
         
       
     
     where R 1 , R 2 , R 3 , R 4 , R 5 , R 5′ , R 6 , X 1 , X 2 , m, and n are described herein.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. provisionalapplication No. 62/098,145, filed Dec. 30, 2014, the entire contents ofwhich are incorporated herein by reference in its entirety.

FIELD OF INVENTION

The present invention is directed to inhibitors of ubiquitin-specificprotease 7 (USP7) useful in the treatment of diseases or disordersassociated with USP7 enzymes. Specifically, the invention is concernedwith compounds and compositions inhibiting USP7, methods of treatingdiseases or disorders associated with USP7, and methods of synthesis ofthese compounds.

BACKGROUND OF THE INVENTION

Ubiquitination is a post translational modification initially identifiedas a crucial component of proteasomal degradation in the ubiquitinproteasome system (UPS). Chains of Ubiquitin (Ub(s)), an 8.5 kDa highlyconserved protein, are covalently attached to substrates to be degradedin the proteasome. (Finley D. “Recognition and processing ofubiquitin-protein conjugates by the proteasome.” Annual review ofbiochemistry 78:477-513, (2009)) The molecular mechanisms by which theUPS acts are also varied, with different chain linkages ofubiquitination controlling protein turnover, enzymatic activity,subcellular localization, and protein-protein interactions of substrateproteins. (Komander D., et. al. “The emerging complexity of proteinubiquitination,” Biochem. Soc. Trans. 37(Pt 5):937-53 (2009))

Ubiquitin-specific protease 7 (USP7) is a Ubiquitin Specific Protease(USP) family deubiquitinase (DUB) that was originally identified as anenzyme that interacted with virally-encoded proteins of the Herpessimplex virus and later the Epstein-Barr virus. (Everett R. D., MeredithM., Orr A., Cross A, Kathoria M., Parkinson J. “A novelubiquitin-specific protease is dynamically associated with the PMLnuclear domain and binds to a herpes virus regulatory protein,” EMBO J.16(7):1519-30 (1997); Holowaty M. N., Zeghouf M., Wu H., et al. “Proteinprofiling with Epstein-Barr nuclear antigen-1 reveals an interactionwith the herpesvirus-associated ubiquitin-specific protease HAUSP/USP7,”J. Biol. Chem. 278(32):29987-94 (2003)) Ubiquitin Specific Proteases(USPs) specifically cleave the isopeptide bond at the carboxy terminusof ubiquitin. In contrast to other DUB classes, which are thought togenerally regulate ubiquitin homeostasis or to be involved inpre-processing of linear ubiquitin chains, USPs remove ubiquitin fromspecific targets. Given this substrate specificity combined with thenumerous roles ubiquitination has in the cell, USPs are importantregulators of a multitude of pathways, ranging from preventing theproteolysis of ubiquitinated substrates, to controlling their nuclearlocalization.

USP7 deubiquitinates a variety of cellular targets involved in differentprocesses related to cancer and metastasis, neurodegenerative diseases,immunological disorders, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, and bacterial infections and diseases.

For example, USP7 has been shown to stabilize DNMT1, a DNAmethyltransferase that maintain epigenetic silencing, to maintain highersteady state-levels of Claspin, a protein involved in ataxiatelangiectasia and Rad3-related (ATR) phosphorylation of Chk1, and toregulate Tip60 protein levels, a histone acetyltransferase andtranscriptional coregulator involved in adipogenesis. (Zhanwen du, SongJ., Wang Y., et al. “DNMT1 stability is regulated by proteinscoordinating deubiquitination and acetylation-driven ubiquitination,”Science Signaling 3(146) (2010); Faustrup H., Bekker-Jensen S., BartekJ., Lukas J., Mail N., Mailand N. “USP7 counteracts SCFbetaTrCP- but notAPCCdh1-mediated proteolysis of Claspin,” The Journal of cell biology184(1):13-9 (2009); Gao Y., Koppen A., Rakhsh M., et al. “Earlyadipogenesis is regulated through USP7-mediated deubiquitination of thehistone acetyltransferase TIP60,” Nature Communications 4:2656 (2013)

In addition to regulating the protein stability of poly-ubiquitinatedtargets, USP7 also acts to control the subcellular localization ofproteins. Mono-ubiquitination of PTEN has been shown to effect itscytoplasmic/nuclear partitioning, where nuclear localization of PTEN isimportant for its tumor suppression activity. (Trotman L. C., Wang X.,Alimonti A., et al. “Ubiquitination regulates PTEN nuclear import andtumor suppression,” Cell 128(1):141-56 (2007); Song M. S., Salmena L.,Carracedo A., et al. “The deubiquitinylation and localization of PTENare regulated by a HAUSP-PML network,” Nature 455(7214):813-7 (2008))USP7 has also been shown to bind and deubiquitinate FOXO4, a member ofthe FOXO subfamily of transcription factors involved in a variety ofcell processes including metabolism, cell cycle regulation apoptosis,and response to oxidative stress, decreasing its nuclear localizationand transcriptional activity. (van der Horst A., van der Horst O., deVries-Smits A. M. M., et al. “FOXO4 transcriptional activity isregulated by monoubiquitination and USP7/HAUSP,” Nat. CellBiol.8(10):1064-73 (2006))

Cellular targets of USP7 also include the tumor suppressor p53 and itsmajor E3 ligase, MDM2, stabilizing p53 via the degradation of MDM2. (LiM., Chen D., Shiloh A., et al. “Deubiquitination of p53 by HAUSP is animportant pathway for p53 stabilization,” Nature 416(6881):648-53(2002); Li M., Brooks C. L., Kon N., Gu W. “A dynamic role of HAUSP inthe p53-Mdm2 pathway,” Mol. Cell. 13(6):879-86 (2004)) Structuralstudies have also shown that the EBNA1 protein encoded by theEpstein-Barr virus interacts at the same binding surface as USP7 on p53,preventing USP7 endogenous cellular activity while recruiting USP7 toviral promoters in order to activate latent viral gene expression.(Saridakis V., et al. “Structure of the p53 binding domain of HAUSP/USP7bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediatedimmortalization,” Mol. Cell. 18(1):25-36 (2005); Sarkari F.,Sanchez-Alcaraz T., Wang S., Holowaty M. N., Sheng Y., Frappier L.“EBNA1-mediated recruitment of a histone H2B deubiquitylating complex tothe Epstein-Barr virus latent origin of DNA replication,” PLoS pathogens5(10) (2009); Sheng Y., et al. “Molecular recognition of p53 and MDM2 byUSP7/HAUSP,” Nat. Struct. Mol. Biol. 13(3):285-91 (2006)) Similarly, thegene product of TSPYL5, a gene frequently amplified in breast cancer andassociated with poor clinical outcome, alters the ubiquitination statusof p53 via its interaction with USP7. (Epping M. T., et al. “TSPYL5suppresses p53 levels and function by physical interaction with USP7,”Nat. Cell Biol. 13(1):102-8 (2011))

Inhibition of USP7 with small molecule inhibitors therefore has thepotential to be a treatment for cancers and other disorders. For thisreason, there remains a considerable need for novel and potent smallmolecule inhibitors of USP7.

SUMMARY OF THE INVENTION

A first aspect of the invention relates to compounds of Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, and tautomer thereof,

wherein:

X₁ is C, S, or S(O);

X₂ is CR₇ or N;

R₁ is H, D, —OH, —SH, —NH₂, —NH(C₁-C₄) alkyl, —N((C₁-C₄) alkyl)₂, or F;

R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₂₅R₂₆, or —OR₂₅, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₁; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₁; or two R₃ together form a(C₃-C₈)spirocycloalkyl optionally substituted with one or more R₂₁; ortwo R₃ together form a spiroheterocycloalkyl optionally substituted withone or more R₂₁; or two R₃ together when on adjacent carbons form anaryl ring optionally substituted with one or more R₂₁; or two R₃together when on adjacent carbons form an heteroaryl ring optionallysubstituted with one or more R₂₁;

R₄ is H, (C₁-C₆) alkyl, CD₃, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₂;

R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—CH₂OH, —CH₂NH₂, or halogen;

R₆ is H, D, or (C₁-C₆) alkyl;

R₇ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, halogen,—NR₁₇C(O)R₈, CN, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—NR₁₇C(O)NR₁₈R₁₉, or —C(O)NR₁₇R₁₈, wherein the alkyl, alkenyl, andalkynyl are optionally substituted with one or more R₂₁;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —(C₁-C₃)-alkylene-O(C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,halogen, —CN, —C(O)R₁₂, —CO(O)R₁₂, —C(O)NR₁₂R₁₃, —S(O)_(q)R₁₂,—S(O)_(q)NR₁₂R₁₃, —NR₁₂S(O)_(q)R₁₃, —(C₀-C₃)-alkylene-NR₁₂R₁₃,—NR₁₂C(O)R₁₃, —NR₁₂C(O)C(O)R₁₃, —NR₁₂C(O)NR₁₂R₁₃, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₂, wherein alkyl, alkylene, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₉;

each R₉ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl,halogen, —OH, —CN, —C(O)R₁₄, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅, —NR₁₄R₁₅,—S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —NR₁₄S(O)_(q)R₁₅, oxo,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or—O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₀; or twoR₉ together with the atoms to which they are attached form a (C₆-C₁₄)aryl ring optionally substituted with one or more R₁₀; or two R₉together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₀; or two R₉ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₀; or two R₉ together with theatoms to which they are attached form a heterocycloalkyl ring optionallysubstituted with one or more R₁₀;

each R₁₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₃C(O)R₂₄,—NR₂₃S(O)_(q)R₂₄, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃,—S(O)_(q)NR₂₃R₂₄, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH,or CN; or

two R₁₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₁; or twoR₁₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₁; or two R₁₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₁; or two R₁₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₁₁;

each R₁₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₂ and R₁₃ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆;

each R₁₄ and R₁₅ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆; or

R₁₄ and R₁₅ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆, whenR₉ is —C(O)NR₁₄R₁₅;

each R₁₆ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

R₁₇ is independently H or (C₁-C₆) alkyl;

R₁₈ is independently (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₀;

R₁₉ is independently H or (C₁-C₆) alkyl;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, CN,(C₆-C₁₄) aryl, —O(C₆-C₁₄) aryl, or heteroaryl, wherein the aryl andheteroaryl are optionally substituted with one or more R₂₁; or

two R₂₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₂₁; or twoR₂₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₂₁; or two R₂₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₂₁; or two R₂₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₂₁;

each R₂₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₂ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, (C₆-C₁₄) aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl,—C(O)NR₂₃R₂₄, —S(O)_(q)NR₂₃R₂₄, —NR₂₃R₂₄, —NR₂₃C(O)NR₂₃R₂₄,—NR₂₃C(O)OR₂₄, —NR₂₃S(O)_(q)R₂₃, —NR₂₃C(O)R₂₄, halogen,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅ or —OH, wherein alkyl,aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, (C₆-C₁₄) aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are optionally substituted one or more substituentsindependently selected from (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆) hydroxyalkyl —OH, CN, —NH₂,—NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

each R₂₃ and R₂₄ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₅ and R₂₆ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore substituents independently selected from (C₁-C₆) alkyl, (C₁-C₆)haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆)hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

q is independently at each occurrence 0, 1, or 2.

Another aspect of the invention relates to a method of treating adisease or disorder associated with modulation of USP7. The methodcomprises administering to a patient in need of a treatment for diseasesor disorders associated with modulation of USP7 an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention is directed to a method of inhibitingUSP7. The method involves administering to a patient in need thereof aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention relates to a method of treating aneurodegenerative disease. The method comprises administering to apatient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating a viralinfection or disease. The method comprises administering to a patient inneed thereof an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating aninflammatory disease or condition. The method comprises administering toa patient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of inducing cellcycle arrest, apoptosis in tumor cells and/or enhanced tumor-specificT-cell immunity. The method comprises contacting the cells with aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof and a pharmaceutically acceptable carrier. The pharmaceuticalacceptable carrier may further include an excipient, diluent, orsurfactant.

Another aspect of the present invention relates to a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the manufacture of amedicament for treating a disease associated with inhibiting USP7.

Another aspect of the present invention relates to the use of a compoundof Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, in the treatment of adisease associated with inhibiting USP7.

The present invention further provides methods of treating a disease ordisorder associated with modulation of USP7 including, cancer andmetastasis, neurodegenerative diseases, immunological disorders,diabetes, bone and joint diseases, osteoporosis, arthritis inflammatorydisorders, cardiovascular diseases, ischemic diseases, viral infectionsand diseases, viral infectivity and/or latency, and bacterial infectionsand diseases, comprising administering to a patient suffering from atleast one of said diseases or disorder a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

The present invention provides inhibitors of USP7 that are therapeuticagents in the treatment of diseases such as cancer and metastasis,neurodegenerative diseases, immunological disorders, diabetes, bone andjoint diseases, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, viral infectivity and/or latency, and bacterial infections anddiseases.

The present invention further provides compounds and compositions withan improved efficacy and safety profile relative to known USP7inhibitors. The present disclosure also provides agents with novelmechanisms of action toward USP7 enzymes in the treatment of varioustypes of diseases including cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases. Ultimately thepresent invention provides the medical community with a novelpharmacological strategy for the treatment of diseases and disordersassociated with USP7 enzymes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds and compositions that arecapable of inhibiting the activity USP7. The invention features methodsof treating, preventing or ameliorating a disease or disorder in whichUSP7 plays a role by administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. The methods of the present inventioncan be used in the treatment of a variety of USP7 dependent diseases anddisorders by inhibiting the activity of USP7 enzymes. Inhibition of USP7provides a novel approach to the treatment, prevention, or ameliorationof diseases including, but not limited to, cancer and metastasis,neurodegenerative diseases, immunological disorders, osteoporosis,arthritis inflammatory disorders, cardiovascular diseases, ischemicdiseases, viral infections and diseases, and bacterial infections anddiseases.

In a first aspect of the invention, the compounds of Formula (I) aredescribed:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein R₁, R₂, R₃, R₄, R₅,R_(5′), R₆, X₁, X₂, m and n are as described herein above.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e., a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, halogen, oxo, —OH, —CN, —COOH, —CH₂CN,—O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, —O—(C₂-C₆) alkenyl, —O—(C₂-C₆) alkynyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂, —OC(O)(C₁-C₆) alkyl,—C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, —NH₂, —NH((C₁-C₆) alkyl),—N((C₁-C₆) alkyl)₂, —NHC(O)(C₁-C₆) alkyl, —C(O)NH(C₁-C₆) alkyl,—S(O)₂(C₁-C₆) alkyl, —S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁-C₆) alkyl)₂.The substituents can themselves be optionally substituted. “Optionallysubstituted” as used herein also refers to substituted or unsubstitutedwhose meaning is described below.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents wherein the substituentsmay connect to the specified group or moiety at one or more positions.For example, an aryl substituted with a cycloalkyl may indicate that thecycloalkyl connects to one atom of the aryl with a bond or by fusingwith the aryl and sharing two or more common atoms.

As used herein, the term “unsubstituted” means that the specified groupbears no substituents.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 3 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to, —H,-halogen, —O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, —O—(C₂-C₆) alkenyl,—O—(C₂-C₆) alkynyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂,—OC(O)(C₁-C₆) alkyl, —C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, —NH₂,NH((C₁-C₆) alkyl), N((C₁-C₆) alkyl)₂, —S(O)₂—(C₁-C₆) alkyl,—S(O)NH(C₁-C₆) alkyl, and —S(O)N((C₁-C₆) alkyl)₂. The substituents canthemselves be optionally substituted. Furthermore when containing twofused rings the aryl groups herein defined may have an unsaturated orpartially saturated ring fused with a fully saturated ring. Exemplaryring systems of these aryl groups include, but are not limited to,phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl,indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, andthe like.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 24 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, or S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl,quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo [1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings theheteroaryl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms. Examples of a (C₁-C₆) alkyl group include,but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl,isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, andisohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms containing a terminal “O” in the chain,i.e., —O(alkyl). Examples of alkoxy groups include without limitation,methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkenyl” group contains at least onedouble bond in the chain. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. Examples ofalkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl,pentenyl, or hexenyl. An alkenyl group can be unsubstituted orsubstituted. Alkenyl, as herein defined, may be straight or branched.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkynyl” group contains at least onetriple bond in the chain. Examples of alkenyl groups include ethynyl,propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynylgroup can be unsubstituted or substituted.

The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical.Any of the above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. As herein defined,alkylene may also be a C₁-C₆ alkylene. An alkylene may further be aC₁-C₄ alkylene. Typical alkylene groups include, but are not limited to,—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

“Cycloalkyl” means monocyclic saturated carbon rings containing 3-18carbon atoms. Examples of cycloalkyl groups include, withoutlimitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

“Cycloalkylalkyl” means monocyclic saturated carbon rings containing3-24 carbon atoms further substituted with (C₁-C₆) alkyl groups. Ingeneral cycloalkylalkyl groups herein described display the followingformula

where m is an integer from 1 to 6 and n is an integer from 1 to 16. Thecycloalkyl ring or carbocycle may be optionally substituted by one ormore substituents, e.g., 1 to 5 substituents, at any point ofattachment. The substituents can themselves be optionally substituted.Examples of cycloalkyl groups include, without limitations, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl,norboranyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl,decahydronaphthalenyl, octahydro-1H-indenyl, cyclopentenyl,cyclohexenyl, cyclohexa-1,4-dienyl, cyclohexa-1,3-dienyl,1,2,3,4-tetrahydronaphthalenyl, octahydropentalenyl,3a,4,5,6,7,7a-hexahydro-1H-indenyl, 1,2,3,3a-tetrahydropentalenyl,bicyclo[3.1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl,bicyclo[2.2.2]octanyl, 6-methylbicyclo[3.1.1]heptanyl,2,6,6-trimethylbicyclo[3.1.1]heptanyl, and derivatives thereof.

“Heterocyclyl” or “heterocycloalkyl” monocyclic rings containing carbonand heteroatoms taken from oxygen, nitrogen, or sulfur and wherein thereis not delocalized π electrons (aromaticity) shared among the ringcarbon or heteroatoms. The heterocycloalkyl ring structure may besubstituted by one or more substituents. The substituents can themselvesbe optionally substituted. Examples of heterocyclyl rings include, butare not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl,thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl,piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl,tropanyl, oxazolidinonyl, and homotropanyl.

The term “hydroxyalkyl” means an alkyl group as defined above, where thealkyl group is substituted with one or more OH groups. Examples ofhydroxyalkyl groups include HO—CH₂—, HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “haloalkyl” as used herein refers to an alkyl group, as definedherein, which is substituted one or more halogen. Examples of haloalkylgroups include, but are not limited to, trifluoromethyl, difluoromethyl,pentafluoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, asdefined herein, which is substituted one or more halogen. Examples ofhaloalkyl groups include, but are not limited to, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond, i.e., C≡N.

The term “amine” as used herein refers to primary (R—NH₂, R≠H),secondary (R₂—NH, R₂≠H) and tertiary (R₃—N, R≠H) amines. A substitutedamine is intended to mean an amine where at least one of the hydrogenatoms has been replaced by the substituent.

The term “amino” as used herein means a substituent containing at leastone nitrogen atom. Specifically, —NH₂, —NH(alkyl) or alkylamino,—N(alkyl)₂ or dialkylamino, amide-, carbamide-, urea, and sulfamidesubstituents are included in the term “amino”.

The term “dialkylamino” as used herein refers to an amino or —NH₂ groupwhere both of the hydrogens have been replaced with alkyl groups, asdefined herein above, i.e., —N(alkyl)₂. The alkyl groups on the aminogroup can be the same or different alkyl groups. Example of alkylaminogroups include, but are not limited to, dimethylamino (i.e., —N(CH₃)₂),diethylamino, dipropylamino, diiso-propylamino, di-n-butylamino,di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino,methyl(butylamino), etc.

“Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ringsystems with both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spriohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another ring carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A (C₃-C₁₂)spirocycloalkyl is a spirocycle containing between 3 and 12 carbonatoms. One or more of the carbon atoms can be substituted with aheteroatom.

The term “spiroheterocycloalkyl” or “spiroheterocyclyl” is understood tomean a spirocycle wherein at least one of the rings is a heterocycle(e.g., at least one of the rings is furanyl, morpholinyl, orpiperadinyl).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesand as individual enantiomers or diastereomers.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fumerate, fiunarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,mucate, napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

The present invention relates to compounds or pharmaceuticallyacceptable salts, hydrates, solvates, prodrugs, stereoisomers, ortautomers thereof, capable of inhibiting USP7, which are useful for thetreatment of diseases and disorders associated with modulation of a USP7enzyme. The invention further relates to compounds, or pharmaceuticallyacceptable salts, hydrates, solvates, prodrugs, stereoisomers, ortautomers thereof, which are useful for inhibiting USP7.

In one embodiment, the compounds of Formula (I) have the structure ofFormula (Ia):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₂₅R₂₆, or —OR₂₅, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

R₄ is H, (C₁-C₆) alkyl, CD₃, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₂;

R₆ is H, D, or (C₁-C₆) alkyl;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —(C₁-C₃)-alkylene-O(C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,halogen, —CN, —C(O)R₁₂, —CO(O)R₁₂, —C(O)NR₁₂R₁₃, —S(O)_(q)R₁₂,—S(O)_(q)NR₁₂R₁₃, —NR₁₂S(O)_(q)R₁₃, —(C₀-C₃)-alkylene-NR₁₂R₁₃,—NR₁₂C(O)R₁₃, —NR₁₂C(O)C(O)R₁₃, —NR₁₂C(O)NR₁₂R₁₃, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₂ wherein alkyl, alkylene, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₉;

each R₉ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl,halogen, —OH, —CN, —C(O)R₁₄, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅, —NR₁₄R₁₅,—S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —NR₁₄S(O)_(q)R₁₅, oxo,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or—O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₀; or

two R₉ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₀; or twoR₉ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₀; or two R₉ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₀; or two R₉ together with theatoms to which they are attached form a heterocycloalkyl ring optionallysubstituted with one or more R₁₀;

each R₁₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₃C(O)R₂₄,—NR₂₃S(O)_(q)R₂₄, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃,—S(O)_(q)NR₂₃R₂₄, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH,or CN; or

two R₁₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₁; or twoR₁₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₁; or two R₁₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₁; or two R₁₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₁₁;

each R₁₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₂ and R₁₃ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆;

each R₁₄ and R₁₅ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆; or

R₁₄ and R₁₅ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆, whenR₉ is —C(O)NR₁₄R₁₅;

each R₁₆ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₂ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, (C₆-C₁₄) aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl,—C(O)NR₂₃R₂₄, —S(O)_(q)NR₂₃R₂₄, —NR₂₃R₂₄, —NR₂₃C(O)NR₂₃R₂₄,—NR₂₃C(O)OR₂₄, —NR₂₃S(O)_(q)R₂₃, —NR₂₃C(O)R₂₄, halogen,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅ or —OH, wherein alkyl,aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, (C₆-C₁₄) aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are optionally substituted one or more substituentsindependently selected from (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆) hydroxyalkyl —OH, CN, —NH₂,—NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

each R₂₃ and R₂₄ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₅ and R₂₆ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore substituents independently selected from (C₁-C₆) alkyl, (C₁-C₆)haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆)hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ib):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₂₅R₂₆, or —OR₂₅, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

R₄ is H, (C₁-C₆) alkyl, CD₃, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₂;

R₆ is H, D, or (C₁-C₆) alkyl;

R₇ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, halogen,—NR₁₇C(O)R₁₈, CN, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—NR₁₇C(O)NR₁₈R₁₉, or —C(O)NR₁₇R₁₈, wherein the alkyl, alkenyl, andalkynyl are optionally substituted with one or more R₂₁;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —(C₁-C₃)-alkylene-O(C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,halogen, —CN, —C(O)R₁₂, —CO(O)R₁₂, —C(O)NR₁₂R₁₃, —S(O)_(q)R₁₂,—S(O)_(q)NR₁₂R₁₃, —NR₁₂S(O)_(q)R₁₃, —(C₀-C₃)-alkylene-NR₁₂R₁₃,—NR₁₂C(O)R₁₃, —NR₁₂C(O)C(O)R₁₃, —NR₁₂C(O)NR₁₂R₁₃, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₂, wherein alkyl, alkylene, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₉;

each R₉ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl,halogen, —OH, —CN, —C(O)R₁₄, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅, —NR₁₄R₁₅,—S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —NR₁₄S(O)_(q)R₁₅, oxo,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or—O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₀; or

two R₉ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₀; or twoR₉ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₀; or two R₉ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₀; or two R₉ together with theatoms to which they are attached form a heterocycloalkyl ring optionallysubstituted with one or more R₁₀;

each R₁₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₃C(O)R₂₄,—NR₂₃S(O)_(q)R₂₄, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃,—S(O)_(q)NR₂₃R₂₄, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH,or CN; or

two R₁₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₁; or twoR₁₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₁; or two R₁₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₁; or two R₁₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₁₁;

each R₁₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₂ and R₁₃ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆;

each R₁₄ and R₁₅ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆; or

R₁₄ and R₁₅ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆, whenR₉ is —C(O)NR₁₄R₁₅;

each R₁₆ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

R₁₇ is independently H or (C₁-C₆) alkyl;

R₁₈ is independently (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₀;

R₁₉ is independently H or (C₁-C₆) alkyl;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, CN,(C₆-C₁₄) aryl, —O(C₆-C₁₄) aryl, or heteroaryl, wherein the aryl andheteroaryl are optionally substituted with one or more R₂₁; or

two R₂₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₂₁; or twoR₂₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₂₁; or two R₂₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₂₁; or two R₂₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₂₁;

each R₂₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₂ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, (C₆-C₁₄) aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl,—C(O)NR₂₃R₂₄, —S(O)_(q)NR₂₃R₂₄, —NR₂₃R₂₄, —NR₂₃C(O)NR₂₃R₂₄,—NR₂₃C(O)OR₂₄, —NR₂₃S(O)_(q)R₂₃, —NR₂₃C(O)R₂₄, halogen,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅ or —OH, wherein alkyl,aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, (C₆-C₁₄) aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are optionally substituted one or more substituentsindependently selected from (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆) hydroxyalkyl —OH, CN, —NH₂,—NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

each R₂₃ and R₂₄ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₅ and R₂₆ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore substituents independently selected from (C₁-C₆) alkyl, (C₁-C₆)haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆)hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ic):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₂₅R₂₆, or —OR₂₅, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₁; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₁; or two R₃ together form a(C₃-C₈) spirocycloalkyl optionally substituted with one or more R₂₁; ortwo R₃ together form a spiroheterocycloalkyl optionally substituted withone or more R₂₁; or two R₃ together when on adjacent carbons form anaryl ring optionally substituted with one or more R₂₁; or two R₃together when on adjacent carbons form an heteroaryl ring optionallysubstituted with one or more R₂₁;

R₄ is H, (C₁-C₆) alkyl, CD₃, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₂;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —(C₁-C₃)-alkylene-O(C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,halogen, —CN, —C(O)R₁₂, —CO(O)R₁₂, —C(O)NR₁₂R₁₃, —S(O)_(q)R₁₂,—S(O)_(q)NR₁₂R₁₃, —NR₁₂S(O)_(q)R₁₃, —(C₀-C₃)-alkylene-NR₁₂R₁₃,—NR₁₂C(O)R₁₃, —NR₁₂C(O)C(O)R₁₃, —NR₁₂C(O)NR₁₂R₁₃, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₂, wherein alkyl, alkylene, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₉;

each R₉ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl,halogen, —OH, —CN, —C(O)R₁₄, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅, —NR₁₄R₁₅,—S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —NR₁₄S(O)_(q)R₁₅, oxo,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or—O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₀; or

two R₉ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₀; or twoR₉ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₀; or two R₉ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₀; or two R₉ together with theatoms to which they are attached form a heterocycloalkyl ring optionallysubstituted with one or more R₁₀;

each R₁₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₃C(O)R₂₄,—NR₂₃S(O)_(q)R₂₄, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃,—S(O)_(q)NR₂₃R₂₄, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH,or CN; or

two R₁₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₁; or twoR₁₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₁; or two R₁₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₁; or two R₁₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₁₁;

each R₁₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₂ and R₁₃ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆;

each R₁₄ and R₁₅ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆; or

R₁₄ and R₁₅ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆, whenR₉ is —C(O)NR₁₄R₁₅;

each R₁₆ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₂ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, (C₆-C₁₄) aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl,—C(O)NR₂₃R₂₄, —S(O)_(q)NR₂₃R₂₄, —NR₂₃R₂₄, —NR₂₃C(O)NR₂₃R₂₄,—NR₂₃C(O)OR₂₄, —NR₂₃S(O)_(q)R₂₃, —NR₂₃C(O)R₂₄, halogen,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅ or —OH, wherein alkyl,aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, (C₆-C₁₄) aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are optionally substituted one or more substituentsindependently selected from (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆) hydroxyalkyl —OH, CN, —NH₂,—NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

each R₂₃ and R₂₄ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₅ and R₂₆ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore substituents independently selected from (C₁-C₆) alkyl, (C₁-C₆)haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆)hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

m is 0, 1, 2, 3, or 4; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₂₅R₂₆, or —OR₂₅, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₁; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₁; or two R₃ together form a(C₃-C₈) spirocycloalkyl optionally substituted with one or more R₂₁; ortwo R₃ together form a spiroheterocycloalkyl optionally substituted withone or more R₂₁; or two R₃ together when on adjacent carbons form anaryl ring optionally substituted with one or more R₂₁; or two R₃together when on adjacent carbons form an heteroaryl ring optionallysubstituted with one or more R₂₁;

R₄ is H, (C₁-C₆) alkyl, CD₃, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₂;

R₇ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, halogen,—NR₁₇C(O)R₁₈, CN, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—NR₁₇C(O)NR₁₈R₁₉, or —C(O)NR₁₇R₁₈, wherein the alkyl, alkenyl, andalkynyl are optionally substituted with one or more R₂₁;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —(C₁-C₃)-alkylene-O(C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,halogen, —CN, —C(O)R₁₂, —CO(O)R₁₂, —C(O)NR₁₂R₁₃, —S(O)_(q)R₁₂,—S(O)_(q)NR₁₂R₁₃, —NR₁₂S(O)_(q)R₁₃, —(C₀-C₃)-alkylene-NR₁₂R₁₃,—NR₁₂C(O)R₁₃, —NR₁₂C(O)C(O)R₁₃, —NR₁₂C(O)NR₁₂R₁₃, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₂, wherein alkyl, alkylene, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₉;

each R₉ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl,halogen, —OH, —CN, —C(O)R₁₄, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅, —NR₁₄R₁₅,—S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —NR₁₄S(O)_(q)R₁₅, OXO,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or—O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₀; or

two R₉ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₀; or twoR₉ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₀; or two R₉ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₀; or two R₉ together with theatoms to which they are attached form a heterocycloalkyl ring optionallysubstituted with one or more R₁₀;

each R₁₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₃C(O)R₂₄,—NR₂₃S(O)_(q)R₂₄, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃,—S(O)_(q)NR₂₃R₂₄, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH,or CN; or

two R₁₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₁; or twoR₁₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₁; or two R₁₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₁; or two R₁₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₁₁;

each R₁₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₂ and R₁₃ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆;

each R₁₄ and R₁₅ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆; or

R₁₄ and R₁₅ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆, whenR₉ is —C(O)NR₁₄R₁₅;

each R₁₆ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

R₁₇ is independently H or (C₁-C₆) alkyl;

R₁₈ is independently (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₀;

R₁₉ is independently H or (C₁-C₆) alkyl;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, CN,(C₆-C₁₄) aryl, —O(C₆-C₁₄) aryl, or heteroaryl, wherein the aryl andheteroaryl are optionally substituted with one or more R₂₁; or

two R₂₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₂₁; or twoR₂₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₂₁; or two R₂₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₂₁; or two R₂₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₂₁;

each R₂₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₂ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, (C₆-C₁₄) aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl,—C(O)NR₂₃R₂₄, —S(O)_(q)NR₂₃R₂₄, —NR₂₃R₂₄, —NR₂₃C(O)NR₂₃R₂₄,—NR₂₃C(O)OR₂₄, —NR₂₃S(O)_(q)R₂₃, —NR₂₃C(O)R₂₄, halogen,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅ or —OH, wherein alkyl,aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, (C₆-C₁₄) aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are optionally substituted one or more substituentsindependently selected from (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆) hydroxyalkyl —OH, CN, —NH₂,—NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

each R₂₃ and R₂₄ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₅ and R₂₆ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore substituents independently selected from (C₁-C₆) alkyl, (C₁-C₆)haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆)hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

m is 0, 1, 2, 3, or 4; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ie):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

Ar is (C₆-C₁₄) aryl or heteroaryl, wherein the aryl and heteroaryl areoptionally substituted with one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₁; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₁; or two R₃ together form a(C₃-C₈) spirocycloalkyl optionally substituted with one or more R₂₁; ortwo R₃ together form a spiroheterocycloalkyl optionally substituted withone or more R₂₁; or two R₃ together when on adjacent carbons form anaryl ring optionally substituted with one or more R₂₁; or two R₃together when on adjacent carbons form an heteroaryl ring optionallysubstituted with one or more R₂₁;

R₄ is H, (C₁-C₆) alkyl, CD₃, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₂;

R₆ is H, D, or (C₁-C₆) alkyl;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —(C₁-C₃)-alkylene-O(C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,halogen, —CN, —C(O)R₁₂, —CO(O)R₁₂, —C(O)NR₁₂R₁₃, —S(O)_(q)R₁₂,—S(O)_(q)NR₁₂R₁₃, —NR₁₂S(O)_(q)R₁₃, —(C₀-C₃)-alkylene-NR₁₂R₁₃,—NR₁₂C(O)R₁₃, —NR₁₂C(O)C(O)R₁₃, —NR₁₂C(O)NR₁₂R₁₃, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₂, wherein alkyl, alkylene, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₉;

each R₉ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl,halogen, —OH, —CN, —C(O)R₁₄, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅, —NR₁₄R₁₅,—S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —NR₁₄S(O)_(q)R₁₅, oxo,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or—O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₀; or

two R₉ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₀; or twoR₉ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₀; or two R₉ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₀; or two R₉ together with theatoms to which they are attached form a heterocycloalkyl ring optionallysubstituted with one or more R₁₀;

each R₁₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₃C(O)R₂₄,—NR₂₃S(O)_(q)R₂₄, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃,—S(O)_(q)NR₂₃R₂₄, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH,or CN; or

two R₁₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₁; or twoR₁₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₁; or two R₁₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₁; or two R₁₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₁₁;

each R₁₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₂ and R₁₃ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆;

each R₁₄ and R₁₅ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆; or

R₁₄ and R₁₅ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆, whenR₉ is —C(O)NR₁₄R₁₅;

each R₁₆ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₂ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, (C₆-C₁₄) aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl,—C(O)NR₂₃R₂₄, —S(O)_(q)NR₂₃R₂₄, —NR₂₃R₂₄, —NR₂₃C(O)NR₂₃R₂₄,—NR₂₃C(O)OR₂₄, —NR₂₃S(O)_(q)R₂₃, —NR₂₃C(O)R₂₄, halogen,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅ or —OH, wherein alkyl,aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, (C₆-C₁₄) aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are optionally substituted one or more substituentsindependently selected from (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆) hydroxyalkyl —OH, CN, —NH₂,—NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

each R₂₃ and R₂₄ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each m is independently at each occurrence 0, 1, 2, 3, or 4; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (If):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

Ar is (C₆-C₁₄) aryl or heteroaryl, wherein the aryl and heteroaryl areoptionally substituted with one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₁; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₁; or two R₃ together form a(C₃-C₈) spirocycloalkyl optionally substituted with one or more R₂₁; ortwo R₃ together form a spiroheterocycloalkyl optionally substituted withone or more R₂₁; or two R₃ together when on adjacent carbons form anaryl ring optionally substituted with one or more R₂₁; or two R₃together when on adjacent carbons form an heteroaryl ring optionallysubstituted with one or more R₂₁;

R₄ is H, (C₁-C₆) alkyl, CD₃, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₂;

R₆ is H, D, or (C₁-C₆) alkyl;

R₇ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, halogen,—NR₁₇C(O)R₁₈, CN, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—NR₁₇C(O)NR₁₈R₁₉, or —C(O)NR₁₇R₁₈, wherein the alkyl, alkenyl, andalkynyl are optionally substituted with one or more R₂₁;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —(C₁-C₃)-alkylene-O(C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,halogen, —CN, —C(O)R₁₂, —CO(O)R₁₂, —C(O)NR₁₂R₁₃, —S(O)_(q)R₁₂,—S(O)_(q)NR₁₂R₁₃, —NR₁₂S(O)_(q)R₁₃, —(C₀-C₃)-alkylene-NR₁₂R₁₃,—NR₁₂C(O)R₁₃, —NR₁₂C(O)C(O)R₁₃, —NR₁₂C(O)NR₁₂R₁₃, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₂, wherein alkyl, alkylene, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₉;

each R₉ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl,halogen, —OH, —CN, —C(O)R₁₄, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅, —NR₁₄R₁₅,—S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —NR₁₄S(O)_(q)R₁₅, OXO,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or—O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₀; or

two R₉ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₀; or twoR₉ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₀; or two R₉ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₀; or two R₉ together with theatoms to which they are attached form a heterocycloalkyl ring optionallysubstituted with one or more R₁₀;

each R₁₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₃C(O)R₂₄,—NR₂₃S(O)_(q)R₂₄, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃,—S(O)_(q)NR₂₃R₂₄, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH,or CN; or

two R₁₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₁; or twoR₁₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₁; or two R₁₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₁; or two R₁₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₁₁;

each R₁₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₂ and R₁₃ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆;

each R₁₄ and R₁₅ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆; or

R₁₄ and R₁₅ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆, whenR₉ is —C(O)NR₁₄R₁₅;

each R₁₆ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

R₁₇ is independently H or (C₁-C₆) alkyl;

R₁₈ is independently (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₀;

R₁₉ is independently H or (C₁-C₆) alkyl;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, CN,(C₆-C₁₄) aryl, —O(C₆-C₁₄) aryl, or heteroaryl, wherein the aryl andheteroaryl are optionally substituted with one or more R₂₁; or

two R₂₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₂₁; or twoR₂₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₂₁; or two R₂₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₂₁; or two R₂₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₂₁;

each R₂₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₂ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, (C₆-C₁₄) aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl,—C(O)NR₂₃R₂₄, —S(O)_(q)NR₂₃R₂₄, —NR₂₃R₂₄, —NR₂₃C(O)NR₂₃R₂₄,—NR₂₃C(O)OR₂₄, —NR₂₃S(O)_(q)R₂₃, —NR₂₃C(O)R₂₄, halogen,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅ or —OH, wherein alkyl,aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, (C₆-C₁₄) aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are optionally substituted one or more substituentsindependently selected from (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆) hydroxyalkyl —OH, CN, —NH₂,—NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

each R₂₃ and R₂₄ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each m is independently at each occurrence 0, 1, 2, 3, or 4; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ig):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

Cy is (C₅-C₈) cycloalkyl or heterocycloalkyl, wherein the cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₁; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₁; or two R₃ together form a(C₃-C₈) spirocycloalkyl optionally substituted with one or more R₂₁; ortwo R₃ together form a spiroheterocycloalkyl optionally substituted withone or more R₂₁; or two R₃ together when on adjacent carbons form anaryl ring optionally substituted with one or more R₂₁; or two R₃together when on adjacent carbons form an heteroaryl ring optionallysubstituted with one or more R₂₁;

R₄ is H, (C₁-C₆) alkyl, CD₃, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₂;

R₆ is H, D, or (C₁-C₆) alkyl;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —(C₁-C₃)-alkylene-O(C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,halogen, —CN, —C(O)R₁₂, —CO(O)R₁₂, —C(O)NR₁₂R₁₃, —S(O)_(q)R₁₂,—S(O)_(q)NR₁₂R₁₃, —NR₁₂S(O)_(q)R₁₃, —(C₀-C₃)-alkylene-NR₁₂R₁₃,—NR₁₂C(O)R₁₃, —NR₁₂C(O)C(O)R₁₃, —NR₁₂C(O)NR₁₂R₁₃, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₂, wherein alkyl, alkylene, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₉;

each R₉ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl,halogen, —OH, —CN, —C(O)R₁₄, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅, —NR₁₄R₁₅,—S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —NR₁₄S(O)_(q)R₁₅, oxo,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or—O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₀; or

two R₉ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₀; or twoR₉ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₀; or two R₉ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₀; or two R₉ together with theatoms to which they are attached form a heterocycloalkyl ring optionallysubstituted with one or more R₁₀;

each R₁₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₃C(O)R₂₄,—NR₂₃S(O)_(q)R₂₄, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃,—S(O)_(q)NR₂₃R₂₄, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH,or CN; or

two R₁₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₁; or twoR₁₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₁; or two R₁₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₁; or two R₁₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₁₁;

each R₁₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₂ and R₁₃ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆;

each R₁₄ and R₁₅ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆; or

R₁₄ and R₁₅ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆, whenR₉ is —C(O)NR₁₄R₁₅;

each R₁₆ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₂ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, (C₆-C₁₄) aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl,—C(O)NR₂₃R₂₄, —S(O)_(q)NR₂₃R₂₄, —NR₂₃R₂₄, —NR₂₃C(O)NR₂₃R₂₄,—NR₂₃C(O)OR₂₄, —NR₂₃S(O)_(q)R₂₃, —NR₂₃C(O)R₂₄, halogen,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅ or —OH, wherein alkyl,aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, (C₆-C₁₄) aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are optionally substituted one or more substituentsindependently selected from (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆) hydroxyalkyl —OH, CN, —NH₂,—NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

each R₂₃ and R₂₄ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each m is independently at each occurrence 0, 1, 2, 3, or 4; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ih):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

Cy is (C₅-C₈) cycloalkyl or heterocycloalkyl, wherein the cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₁; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₁; or two R₃ together form a(C₃-C₈) spirocycloalkyl optionally substituted with one or more R₂₁; ortwo R₃ together form a spiroheterocycloalkyl optionally substituted withone or more R₂₁; or two R₃ together when on adjacent carbons form anaryl ring optionally substituted with one or more R₂₁; or two R₃together when on adjacent carbons form an heteroaryl ring optionallysubstituted with one or more R₂₁;

R₄ is H, (C₁-C₆) alkyl, CD₃, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₂;

R₆ is H, D, or (C₁-C₆) alkyl;

R₇ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, halogen,—NR₁₇C(O)R₁₈, CN, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—NR₁₇C(O)NR₁₈R₁₉, or —C(O)NR₁₇R₁₈, wherein the alkyl, alkenyl, andalkynyl are optionally substituted with one or more R₂₁;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —(C₁-C₃)-alkylene-O(C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,halogen, —CN, —C(O)R₁₂, —CO(O)R₁₂, —C(O)NR₁₂R₁₃, —S(O)_(q)R₁₂,—S(O)_(q)NR₁₂R₁₃, —NR₁₂S(O)_(q)R₁₃, —(C₀-C₃)-alkylene-NR₁₂R₁₃,—NR₁₂C(O)R₁₃, —NR₁₂C(O)C(O)R₁₃, —NR₁₂C(O)NR₁₂R₁₃, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₂, wherein alkyl, alkylene, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₉;

each R₉ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl,halogen, —OH, —CN, —C(O)R₁₄, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅, —NR₁₄R₁₅,—S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —NR₁₄S(O)_(q)R₁₅, oxo,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or—O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₀; or

two R₉ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₀; or twoR₉ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₀; or two R₉ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₀; or two R₉ together with theatoms to which they are attached form a heterocycloalkyl ring optionallysubstituted with one or more R₁₀;

each R₁₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₃C(O)R₂₄,—NR₂₃S(O)_(q)R₂₄, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃,—S(O)_(q)NR₂₃R₂₄, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH,or CN; or

two R₁₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₁; or twoR₁₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₁; or two R₁₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₁; or two R₁₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₁₁;

each R₁₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₂ and R₁₃ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆;

each R₁₄ and R₁₅ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆; or

R₁₄ and R₁₅ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆, whenR₉ is —C(O)NR₁₄R₁₅;

each R₁₆ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

R₁₇ is independently H or (C₁-C₆) alkyl;

R₁₈ is independently (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₀;

R₁₉ is independently H or (C₁-C₆) alkyl;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, CN,(C₆-C₁₄) aryl, —O(C₆-C₁₄) aryl, or heteroaryl, wherein the aryl andheteroaryl are optionally substituted with one or more R₂₁; or

two R₂₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₂₁; or twoR₂₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₂₁; or two R₂₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₂₁; or two R₂₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₂₁;

each R₂₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₂ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, (C₆-C₁₄) aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl,—C(O)NR₂₃R₂₄, —S(O)_(q)NR₂₃R₂₄, —NR₂₃R₂₄, —NR₂₃C(O)NR₂₃R₂₄,—NR₂₃C(O)OR₂₄, —NR₂₃S(O)_(q)R₂₃, —NR₂₃C(O)R₂₄, halogen,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅ or —OH, wherein alkyl,aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, (C₆-C₁₄) aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are optionally substituted one or more substituentsindependently selected from (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆) hydroxyalkyl —OH, CN, —NH₂,—NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

each R₂₃ and R₂₄ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each m is independently at each occurrence 0, 1, 2, 3, or 4; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ii):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₂₅R₂₆, or —OR₂₅, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₁; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₁; or two R₃ together form a(C₃-C₈) spirocycloalkyl optionally substituted with one or more R₂₁; ortwo R₃ together form a spiroheterocycloalkyl optionally substituted withone or more R₂₁; or two R₃ together when on adjacent carbons form anaryl ring optionally substituted with one or more R₂₁; or two R₃together when on adjacent carbons form an heteroaryl ring optionallysubstituted with one or more R₂₁;

R₄ is H, (C₁-C₆) alkyl, CD₃, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₂;

R₆ is H, D, or (C₁-C₆) alkyl;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —(C₁-C₃)-alkylene-O(C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,halogen, —CN, —C(O)R₁₂, —CO(O)R₁₂, —C(O)NR₁₂R₁₃, —S(O)_(q)R₁₂,—S(O)_(q)NR₁₂R₁₃, —NR₁₂S(O)_(q)R₁₃, —(C₀-C₃)-alkylene-NR₁₂R₁₃,—NR₁₂C(O)R₁₃, —NR₁₂C(O)C(O)R₁₃, —NR₁₂C(O)NR₁₂R₁₃, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, —SF₅, or —OR₁₂, wherein alkyl, alkylene, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₉;

each R₉ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl, heteroaryl,halogen, —OH, —CN, —C(O)R₁₄, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅, —NR₁₄R₁₅,—S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —NR₁₄S(O)_(q)R₁₅, oxo,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or—O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₀; or

two R₉ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₀; or twoR₉ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₀; or two R₉ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₀; or two R₉ together with theatoms to which they are attached form a heterocycloalkyl ring optionallysubstituted with one or more R₁₀;

each R₁₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₃C(O)R₂₄,—NR₂₃S(O)_(q)R₂₄, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃,—S(O)_(q)NR₂₃R₂₄, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH,or CN; or

two R₁₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₁₁; or twoR₁₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₁₁; or two R₁₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₁; or two R₁₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₁₁;

each R₁₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₁₂ and R₁₃ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆;

each R₁₄ and R₁₅ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₁₆; or

R₁₄ and R₁₅ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₆, whenR₉ is —C(O)NR₁₄R₁₅;

each R₁₆ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

R₁₇ is independently H or (C₁-C₆) alkyl;

R₁₈ is independently (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₀;

R₁₉ is independently H or (C₁-C₆) alkyl;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, CN,(C₆-C₁₄) aryl, —O(C₆-C₁₄) aryl, or heteroaryl, wherein the aryl andheteroaryl are optionally substituted with one or more R₂₁; or

two R₂₀ together with the atoms to which they are attached form a(C₆-C₁₄) aryl ring optionally substituted with one or more R₂₁; or twoR₂₀ together with the atoms to which they are attached form a heteroarylring optionally substituted with one or more R₂₁; or two R₂₀ togetherwith the atoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₂₁; or two R₂₀ together withthe atoms to which they are attached form a heterocycloalkyl ringoptionally substituted with one or more R₂₁;

each R₂₁ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₂ is independently at each occurrence D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, (C₆-C₁₄) aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl,—C(O)NR₂₃R₂₄, —S(O)_(q)NR₂₃R₂₄, —NR₂₃R₂₄, —NR₂₃C(O)NR₂₃R₂₄,—NR₂₃C(O)OR₂₄, —NR₂₃S(O)_(q)R₂₃, —NR₂₃C(O)R₂₄, halogen,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅ or —OH, wherein alkyl,aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, (C₆-C₁₄) aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are optionally substituted one or more substituentsindependently selected from (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆) hydroxyalkyl —OH, CN, —NH₂,—NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

each R₂₃ and R₂₄ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl;

each R₂₅ and R₂₆ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore substituents independently selected from (C₁-C₆) alkyl, (C₁-C₆)haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆)hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂;

each m is independently at each occurrence 0, 1, 2, 3, or 4; and

q is independently at each occurrence 0, 1, or 2.

In some embodiments of the Formulae above, X₁ is C, S, or S(O). Inanother embodiment, X₁ is C or S(O). In yet another embodiment, X₁ is C.

In some embodiments of the Formulae above, X₂ is CR₇. In anotherembodiment, X₂ is N.

In some embodiments of the Formulae above, R₁ is H, D, —OH, —SH, —NH₂,—NH(C₁-C₄) alkyl, —N((C₁-C₄) alkyl)₂, or F. In another embodiment, R₁ isH, D, —OH, or F. In yet another embodiment, R₁ is H, —OH, or F. Inanother embodiment, R₁ is —OH, or F. In yet another embodiment, R₁ is—OH.

In some embodiments of the Formulae above, R₂ is (C₁-C₈) alkyl, (C₆-C₁₄)aryl, heteroaryl, (C₅-C₈) cycloalkyl, heterocycloalkyl, —NR₂₅R₂₆, or—OR₂₅, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₈. Inanother embodiment, R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl,(C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈. In yet another embodiment, R₂ is (C₁-C₈) alkyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkylare optionally substituted with one to three R₈.

In some embodiments of the Formulae above, R₃ is selected from D,(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₁. Inanother embodiment, R₃ is selected from D, (C₁-C₆) alkyl, optionallysubstituted with one or more R₂₁. In yet another embodiment, R₃ isselected from D or (C₁-C₆) alkyl, optionally substituted with one ormore R₂₁. In another embodiment, R₃ is selected from D or (C₁-C₄) alkyl,optionally substituted with one or more R₂₁.

In another embodiment, two R₃ together when on adjacent carbons form a(C₃-C₈) cycloalkyl optionally substituted with one or more R₂₁. In yetanother embodiment, two R₃ together form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₂₁. In another embodiment, twoR₃ together form a spiroheterocycloalkyl optionally substituted with oneor more R₂₁. In yet another embodiment, two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₂₁.In another embodiment, two R₃ together when on adjacent carbons form anheteroaryl ring optionally substituted with one or more R₂₁.

In some embodiments of the Formulae above, R₄ is H, (C₁-C₆) alkyl, CD₃,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl areoptionally substituted with one or more R₂₂. In another embodiment, R₄is H, (C₁-C₆) alkyl, CD₃, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R₂₂. Inyet another embodiment, R₄ is H, (C₁-C₆) alkyl, or CD₃. In anotherembodiment, R₄ is H, (C₁-C₃) alkyl, or CD₃. In yet another embodiment,R₄ is H, methyl, ethyl, propyl, iso-propyl, or CD₃.

In some embodiments of the Formulae above, R₅ is H, D, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, —CH₂OH, —CH₂NH₂, or halogen. In another embodiment,R₅ is H, D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)haloalkoxy, —CH₂OH, —CH₂NH₂, or halogen. In yet another embodiment, R₅is H, D, (C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, (C₁-C₃)haloalkoxy, —CH₂OH, —CH₂NH₂, or halogen. In another embodiment, R₅ is H,D, (C₁-C₃) alkyl, —CH₂OH, —CH₂NH₂, or halogen. In yet anotherembodiment, R₅ is H, D, methyl, ethyl, propyl, iso-propyl, —CH₂OH,—CH₂NH₂, or halogen.

In some embodiments of the Formulae above, R_(5′) is H, D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —CH₂OH, —CH₂NH₂, or halogen. In anotherembodiment, R_(5′) is H, D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, —CH₂OH, —CH₂NH₂, or halogen. In yetanother embodiment, R_(5′) is H, D, (C₁-C₃) alkyl, (C₁-C₃) alkoxy,(C₁-C₃) haloalkyl, (C₁-C₃) haloalkoxy, —CH₂OH, —CH₂NH₂, or halogen. Inanother embodiment, R_(5′) is H, D, (C₁-C₃) alkyl, —CH₂OH, —CH₂NH₂, orhalogen. In yet another embodiment, R_(5′) is H, D, methyl, ethyl,propyl, iso-propyl, CH₂OH, —CH₂NH₂, or halogen.

In some embodiments of the Formulae above, R₆ is H, D, or (C₁-C₆) alkyl.In another embodiment, R₆ is H, D, or (C₁-C₃) alkyl. In yet anotherembodiment, R₆ is H, D, methyl, ethyl, propyl, or iso-propyl.

In some embodiments of the Formulae above, R₇ is H, D, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, halogen, —NR₁₇C(O)R₁₈, CN,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —NR₁₇C(O)NR₁₈R₁₉, or—C(O)NR₁₇R₁₈, wherein the alkyl, alkenyl, and alkynyl are optionallysubstituted with one or more R₂₁. In another embodiment, R₇ is H, D,(C₁-C₆) alkyl, halogen, —NR₁₇C(O)R₁₈, —NR₁₇C(O)NR₁₈R₁₉, or —C(O)NR₁₇R₁₈,wherein the alkyl is optionally substituted with one or more R₂₁. In yetanother embodiment, R₇ is H, D, (C₁-C₆) alkyl, halogen, —NR₁₇C(O)R₁₈, or—NR₁₇C(O)NR₁₈R₁₉, wherein the alkyl is optionally substituted with oneor more R₂₁. In another embodiment, R₇ is H, halogen, —NR₁₇C(O)R₁₈, or—NR₁₇C(O)NR₁₈R₁₉.

In some embodiments of the Formulae above, R₈ is D, (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocycloalkyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₂, —CO(O)R₁₂,—C(O)NR₁₂R₁₃, —S(O)_(q)R₁₂, —S(O)_(q)NR₁₂R₁₃, —NR₁₂S(O)_(q)R₁₃,—(C₀-C₃)-alkylene-NR₁₂R₁₃, —NR₁₂C(O)R₁₃, —NR₁₂C(O)C(O)R₁₃,—NR₁₂C(O)NR₁₂R₁₃, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, or—OR₁₂, wherein alkyl, alkylene, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₉. Inanother embodiment, R₈ is (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocycloalkyl,—C(O)R₁₂, —S(O)_(q)R₁₂, —(C₀-C₃)-alkylene-NR₁₂R₁₃, or —OR₁₂, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₉. In yet another embodiment, R₈ is(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,halogen, CN, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₁₀) cycloalkyl,heterocycloalkyl, —C(O)R₁₂, —S(O)_(q)R₁₂, —(C₀-C₃)-alkylene-NR₁₂R₁₃, or—OR₁₂, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one to three R₉.

In some embodiments of the Formulae above, R₉ is D, (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, (C₆-C₁₄) aryl,heteroaryl, halogen, —OH, —CN, —C(O)R₁₄, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅,—NR₁₄R₁₅, —S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —NR₁₄S(O)_(q)R₁₅, oxo,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —O-aryl, CN, or—O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₀. Inanother embodiment, R₉ is (C₁-C₆) alkyl, (C₁-C₆) alkoxy, halogen, CN,—S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅, (C₆-C₁₄)aryl, heteroaryl, (C₃-C₈) cycloalkyl, or heterocycloalkyl, wherein thealkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more R₁₀. In yet another embodiment, R₉ is(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,halogen, CN, —S(O)_(q)R₁₄, —S(O)_(q)NR₁₄R₁₅, —C(O)NR₁₄R₁₅, —NR₁₄C(O)R₁₅,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl areoptionally substituted with one to three R₁₀.

In another embodiment, two R₉ together with the atoms to which they areattached form a (C₆-C₁₄) aryl ring optionally substituted with one ormore R₁₀. In yet another embodiment, two R₉ together with the atoms towhich they are attached form a heteroaryl ring optionally substitutedwith one or more R₁₀. In another embodiment, two R₉ together with theatoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₀. In yet another embodiment,two R₉ together with the atoms to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₀.

In some embodiments of the Formulae above, R₁₀ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₃C(O)R₂₄,—NR₂₃S(O)_(q)R₂₄, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃,—S(O)_(q)NR₂₃R₂₄, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, —OH,or CN. In another embodiment, R₁₀ is (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN. In yetanother embodiment, R₀ is (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, halogen, —OH, or CN.

In another embodiment, R₁₀ together with the atoms to which they areattached form a (C₆-C₁₄) aryl ring optionally substituted with one ormore R₁₁. In yet another embodiment, two R₁₀ together with the atoms towhich they are attached form a heteroaryl ring optionally substitutedwith one or more R₁₁. In another embodiment, two R₁₀ together with theatoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₁₁. In yet another embodiment,two R₁₀ together with the atoms to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₁.

In some embodiments of the Formulae above, R₁₁ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN. In another embodiment, R₁₁ is (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, halogen, —OH, —NH₂, or CN.

In some embodiments of the Formulae above, R₁₂ is H, (C₁-C₆) alkyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl areoptionally substituted with one or more R₁₆. In another embodiment, R₁₂is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R₁₆.

In some embodiments of the Formulae above, R₁₃ is H, (C₁-C₆) alkyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl areoptionally substituted with one or more R₁₆. In another embodiment, R₁₃is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R₁₆.

In some embodiments of the Formulae above, R₁₄ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₁₆. In another embodiments of the Formulae above, R₁₄ is H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₁₆.

In another embodiment, R₁₄ and R₁₅ together with the nitrogen to whichthey are attached form a heterocycloalkyl ring optionally substitutedwith one or more R₁₆, when R₉ is —C(O)NR₁₄R₁₅.

In some embodiments of the Formulae above, R₁₆ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN. Inanother embodiment, R₁₆ is (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, halogen, —OH, or CN.

In some embodiments of the Formulae above, R₁₇ is independently H or(C₁-C₆) alkyl. In another embodiment, R₁₇ is independently H or (C₁-C₃)alkyl. In yet another embodiment, R₁₇ is independently H, methyl, ethyl,propyl, or iso-propyl.

In some embodiments of the Formulae above, R₁₈ is independently (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₀. Inanother embodiment, R₁₈ is independently (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one to three R₂₀.

In some embodiments of the Formulae above, R₁₉ is H or (C₁-C₆) alkyl. Inanother embodiment, R₁₉ is H or (C₁-C₃) alkyl. In yet anotherembodiment, R₁₇ is independently H, methyl, ethyl, propyl, oriso-propyl.

In some embodiments of the Formulae above, R₂₀ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, CN,(C₆-C₁₄) aryl, —O(C₆-C₁₄) aryl, or heteroaryl, wherein the aryl andheteroaryl are optionally substituted with one or more R₂₁. In anotherembodiment, R₂₀ is (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, halogen, —OH, CN, (C₆-C₁₄) aryl, —O(C₆-C₁₄) aryl, orheteroaryl, wherein the aryl and heteroaryl are optionally substitutedwith one to three R₂₁.

In another embodiment, two R₂₀ together with the atoms to which they areattached form a (C₆-C₁₄) aryl ring optionally substituted with one ormore R₂₁. In yet another embodiment, R₂₀ together with the atoms towhich they are attached form a heteroaryl ring optionally substitutedwith one or more R₂₁. In another embodiment, two R₂₀ together with theatoms to which they are attached form a (C₅-C₈) cycloalkyl ringoptionally substituted with one or more R₂₁. In yet another embodiment,two R₂₀ together with the atoms to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₂₁.

In some embodiments of the Formulae above, R₂₁ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN.

In some embodiments of the Formulae above, R₂₂ is D, (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, (C₆-C₁₄) aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)(C₁-C₆) alkyl, —C(O)O(C₁-C₆) alkyl,—C(O)NR₂₃R₂₄, —S(O)_(q)NR₂₃R₂₄, —NR₂₃R₂₄, —NR₂₃C(O)NR₂₃R₂₄,—NR₂₃C(O)OR₂₄, —NR₂₃S(O)_(q)R₂₃, —NR₂₃C(O)R₂₄, halogen,—P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅ or —OH, wherein alkyl,aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, (C₆-C₁₄) aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are optionally substituted one or more substituentsindependently selected from (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆) hydroxyalkyl —OH, CN, —NH₂,—NH(C₁-C₄) alkyl, or —N((C₁-C₄) alkyl)₂.

In some embodiments of the Formulae above, R₂₃ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl.

In some embodiments of the Formulae above, R₂₄ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl.

In some embodiments of the Formulae above, R₂₅ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl, or—N((C₁-C₄) alkyl)₂. In another embodiment, R₂₅ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one to three substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl, or—N((C₁-C₄) alkyl)₂.

In some embodiments of the Formulae above, R₂₆ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl, or—N((C₁-C₄) alkyl)₂. In another embodiment, R₂₆ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one to three substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, (C₁-C₆) hydroxyalkyl, —OH, CN, —NH₂, —NH(C₁-C₄) alkyl, or—N((C₁-C₄) alkyl)₂.

In some embodiments of the Formulae above, m is 0, 1, 2, 3, or 4. Inanother embodiment, m is 0, 1, 2 or 3. In yet another embodiment, m is0, 1, or 2. In another embodiment, m is 0 or 1.

In some embodiments of the Formulae above, n is 0, 1, 2, or 3. Inanother embodiment, n is 0, 1, or 2. In yet another embodiment, n is 1.

In some embodiments of the Formulae above, q is 0. In some embodimentsof the Formulae above, q is 1. In some embodiments of the Formulaeabove, q is 2.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₂ is N.

In some embodiments of the Formulae above, X₂ is CR₇. In anotherembodiment, X₂ is N.

In some embodiments of the Formulae above, R₁ is —OH.

In some embodiments of the Formulae above, R₄ is H or (C₁-C₆) alkyl.

In some embodiments of the Formulae above, R₅ is H.

In some embodiments of the Formulae above, R_(5′) is H.

In some embodiments of the Formulae above, R₆ is H.

In some embodiments of the Formulae above, R₇ is H, halogen,—NR₁₇C(O)R₁₈, or —NR₁₇C(O)NR₁₈R₁₉.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is C and X₂ is N. In yet another embodiment, X₁ is C, X₂is N, and R₁ is —OH. In another embodiment, X₁ is C, X₂ is N, R₁ is —OH,and R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₈. Inyet another embodiment, X₁ is C, X₂ is N, R₁ is —OH, R₂ is (C₁-C₈)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₈ and R₄is H or (C₁-C₃) alkyl. In another embodiment, X₁ is C, X₂ is N, R₁ is—OH, R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₈, R₄is H or (C₁-C₃) alkyl, and R₅ is H. In yet another embodiment, X₁ is C,X₂ is N, R₁ is —OH, R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl,(C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈, R₄ is H or (C₁-C₃) alkyl, R₅ is H and R_(5′) is H.In another embodiment, X₁ is C, X₂ is N, R₁ is —OH, R₂ is (C₁-C₈) alkyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkylare optionally substituted with one or more R₈, R₄ is H or (C₁-C₃)alkyl, R₅ is H, R_(5′) is H, and R₆ is H. In yet another embodiment, X₁is C, X₂ is N, R₁ is —OH, R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₈, R₄ is H or (C₁-C₃) alkyl, R₅ is H,R_(5′) is H, R₆ is H, and R₇ is H, halogen, —NR₁₇C(O)R₁₈, or—NR₁₇C(O)NR₁₈R₁₉. In another embodiment, X₁ is C, X₂ is N, R₁ is —OH, R₂is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₈, R₄ is Hor (C₁-C₃) alkyl, R₅ is H, R_(5′) is H, R₆ is H, R₇ is H, halogen,—NR₁₇C(O)R₁₈, or —NR₁₇C(O)NR₁₈R₁₉, and m is 0 or 1. In anotherembodiment, X₁ is C, X₂ is N, R₁ is —OH, R₂ is (C₁-C₈) alkyl, (C₆-C₁₄)aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₈, R₄ is H or (C₁-C₃) alkyl, R₅ is H,R_(5′) is H, R₆ is H, R₇ is H, halogen, —NR₁₇C(O)R₁₈, or—NR₁₇C(O)NR₁₈R₁₉, m is 0 or 1, and n is 1.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is C and X₂ is CR₇. In yet another embodiment, X₁ is C,X₂ is CR₇, and R₁ is —OH. In another embodiment, X₁ is C, X₂ is CR₇, R₁is —OH, and R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₈. In yet another embodiment, X₁ is C, X₂ is CR₇, R₁ is —OH, R₂ is(C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₈ and R₄is H or (C₁-C₃) alkyl. In another embodiment, X₁ is C, X₂ is CR₇, R₁ is—OH, R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₈, R₄is H or (C₁-C₃) alkyl, and R₅ is H. In yet another embodiment, X₁ is C,X₂ is CR₇, R₁ is —OH, R₂ is (C₁-C₈) alkyl, (C₆-C₁₄) aryl, heteroaryl,(C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈, R₄ is H or (C₁-C₃) alkyl, R₅ is H and R_(5′) is H.In another embodiment, X₁ is C, X₂ is CR₇, R₁ is —OH, R₂ is (C₁-C₈)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₈, R₄ is Hor (C₁-C₃) alkyl, R₅ is H, R_(5′) is H and R₆ is H. In yet anotherembodiment, X₁ is C, X₂ is CR₇, R₁ is —OH, R₂ is (C₁-C₈) alkyl, (C₆-C₁₄)aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₈, R₄ is H or (C₁-C₃) alkyl, R₅ is H,R_(5′) is H, R₆ is H, and R₇ is H, halogen, —NR₁₇C(O)R₁₈, or—NR₁₇C(O)NR₁₈R₁₉. In yet another embodiment, X₁ is C, X₂ is CR₇, R₁ is—OH, R₂ is (C₁—C) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₈, R₄is H or (C₁-C₃) alkyl, R₅ is H, R_(5′) is H, R₆ is H, R₇ is H, halogen,—NR₁₇C(O)R₁₈, or —NR₁₇C(O)NR₁₈R₁₉, and m is 0 or 1. In anotherembodiment, X₁ is C, X₂ is CR₇, R₁ is —OH, R₂ is (C₁-C₈) alkyl, (C₆-C₁₄)aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₈, R₄ is H or (C₁-C₃) alkyl, R₅ is H,R_(5′) is H, R₆ is H, R₇ is H, halogen, —NR₁₇C(O)R₁₈, or—NR₁₇C(O)NR₁₈R₁₉, m is 0 or 1, and n is 1.

-   Non-limiting illustrative compounds of the invention include:-   3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-1);-   3-((1-([1,1′-biphenyl]-2-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-2);-   3-((4-hydroxy-1-(2-(thiophen-3-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-3);-   3-((1-(3′-fluoro-[1,1′-biphenyl]-2-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-4);-   3-((1-(3-(benzo[d][1,3]dioxol-5-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-5);-   3-((4-hydroxy-1-(2′-methyl-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-6);-   3-((4-hydroxy-1-(4′-methyl-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-7);-   3-((4-hydroxy-1-(4′-methoxy-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-8);-   3-((1-(4′-fluoro-3′-methyl-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-9);-   3-((4-hydroxy-1-(3′-methoxy-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-10);-   3-((1-([1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-11);-   3-((1-(4′-chloro-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-12);-   3-((1-(3′-chloro-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrol[2,1-f][1,2,4]triazin-4(3H)-one    (I-13);-   3-((4-hydroxy-1-(4′-isopropyl-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrol[2,1-f][1,2,4]triazin-4(3H)-one    (I-14);-   3-((4-hydroxy-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-15);-   3′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-4-carboxamide    (I-16);-   3-((1-(3′,4′-dimethyl-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-17);-   3′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-2-carbonitrile    (I-18);-   3′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonitrile    (I-19);-   3-((4-hydroxy-1-(3-(5-methylthiophen-2-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-20);-   3-((4-hydroxy-1-(3-(quinolin-6-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-21);-   3-((4-hydroxy-1-(3-(imidazo[1,2-a]pyridin-6-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-22);-   3-((1-(3-(benzo[d]thiazol-5-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-23);-   3-((4-hydroxy-1-(3-(5-methyl-1H-indazol-4-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-24);-   3-((4-hydroxy-1-(3-(1-methyl-1H-indol-2-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-25);-   N-cyclopentyl-3′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-3-carboxamide    (I-26);-   3-((4-hydroxy-1-(3-(thiophen-2-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-27);-   3-((4-hydroxy-1-(3-(thiophen-3-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-28);-   3-((1-(2′-fluoro-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-29);-   3-((1-(3′-fluoro-[1,1′-biphenyl]-3-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-30);-   2-(4-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)phenyl)-2-methylpropanenitrile    (I-31);-   3-((4-hydroxy-1-(2-phenyloxazole-5-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-32);-   3-((1-(1-(benzo[d]oxazol-2-yl)piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-33);-   3-((1-(3-(1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-34);-   3-((4-hydroxy-1-(3′-methoxy-[1,1′-biphenyl]-4-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-35);-   3-((1-([1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-36);-   3-((1-(3′-ethoxy-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-37);-   4′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide    (I-38);-   3-((4-hydroxy-1-(4′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-39);-   3-((1-(2′,5′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-40);-   N-ethyl-4′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-4-carboxamide    (I-41);-   3-((4-hydroxy-1-(4-(quinolin-3-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-42);-   3-((4-hydroxy-1-(4-(quinolin-6-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-43);-   3-((1-(3′,5′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-44);-   3-((4-hydroxy-1-(4-(2-methylquinolin-6-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-45);-   3-((4-hydroxy-1-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-46);-   3-((1-(4-(benzo[d]oxazol-5-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-47);-   3-((1-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-48);-   6-chloro-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-49);-   3-((1-(3-chloro-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-50);-   3-((1-(3-chloro-4′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-51);-   3-((4-hydroxy-1-(4′-(piperidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-52);-   3-((1-(2-benzyl-3,3-dimethylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-53);-   2-benzyl-3-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidin-1-yl)-3-oxopropanenitrile    (I-54);-   3-((4-hydroxy-1-(4-(2-phenylpropan-2-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-55);-   (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-56);-   3-((1-(3-(1H-pyrrol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-57);-   3-((4-hydroxy-1-(2-(1,2,3,4-tetrahydronaphthalen-2-yl)acetyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-58);-   3-((4-hydroxy-1-(4-(thiazol-4-yl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-59);-   3-((1-(2-benzylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-60);-   3-((4-hydroxy-1-(4-(phenyl    sulfonyl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-61);-   3-((4-hydroxy-1-(4-(phenylthio)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-62);-   3-((4-hydroxy-1-(2-methyl-3-phenylpropanoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-63);-   3-((1-(4-((1H-benzo[d]imidazol-1-yl)methyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-64);-   3-((1-(4-((1H-pyrazol-1-yl)methyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-65);-   3-((4-hydroxy-1-(4-((5-methyl-1H-tetrazol-1-yl)methyl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-66);-   3-((4-hydroxy-1-(4-((5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-67);-   3-((1-(4-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-68);-   3-((1-(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-69);-   3-((4-hydroxy-1-(4-(thiophen-2-ylmethyl)benzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-70);-   3-((1-(4-benzoylbenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-71);-   3-((1-(4-(ethyl(phenyl)amino)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-72);-   4-(4-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)piperazin-1-yl)benzonitrile    (I-73);-   3-((4-hydroxy-1-(4-(4-(methyl    sulfonyl)phenyl)piperazine-1-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-74);-   3-((1-(2-chloro-4-(piperidin-1-ylmethyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-75);-   3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-76);-   3-((4-hydroxy-1-(2-methyl-3-phenylpropanoyl)piperidin-4-yl)methyl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-77);-   3′-chloro-4′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide    (I-78);-   3-((1-(3-chloro-4′-(piperidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-79);-   3-((4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-80);-   (R)—N-(3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)acetamide    (I-81);-   (R)-1-(3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-methylurea    (I-82);-   3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-83);-   3-((4-hydroxy-1-(2-methyl-3-phenylpropanoyl)piperidin-4-yl)methyl)-6-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one    (I-84);-   1-(3-chlorophenyl)-3-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)urea    (I-85);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(m-tolyl)urea (I-86);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(4-fluorobenzyl)urea (I-87);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(4-fluorophenyl)urea (I-88);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(p-tolyl)urea (I-89);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(2,3-dihydro-1H-inden-5-yl)urea    (I-90);-   1-(4-chlorobenzyl)-3-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)urea    (I-91);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(4-methylbenzyl)urea (I-92);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(3,5-difluorophenyl)urea (I-93);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(2-fluorobenzyl)urea (I-94);-   (R)-1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(1-phenylethyl)urea (I-95);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(3-fluorophenyl)urea (I-96);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(3-fluoro-2-methylphenyl)urea (I-97);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(2,3-dimethylphenyl)urea (I-98);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(2,4-dimethylphenyl)urea (I-99);-   1-(4-cyanophenyl)-3-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)urea    (I-100);-   1-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3-(3-methoxyphenyl)urea (I-101);-   N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-4-(trifluoromethyl)benzamide (I-102);-   N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-2-(2,6-dichlorophenyl)acetamide (I-103);-   N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-2-(4-(trifluoromethoxy)phenoxy)acetamide    (I-104);-   N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-2-(3,4-dichlorophenoxy)acetamide    (I-105);-   N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-2-(2,3-dichlorophenoxy)acetamide    (I-106);-   N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-3,4-dimethylbenzamide (I-107);-   3-chloro-N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-4-methylbenzamide    (I-108);-   N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-2,5-dimethylbenzamide (I-109);-   N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-2-(trifluoromethoxy)benzamide (I-110);-   2,4-dichloro-N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)benzamide    (I-111);-   N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo    [2,1-f][1,2,4]triazin-6-yl)-2-phenylthiazole-4-carboxamide (I-112);-   3-(4-chlorophenyl)-N-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)butanamide    (I-113);-   N-(4′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-2-yl)methacrylamide    (I-114);-   3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-7-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one    (I-115);-   3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one    (I-116);-   3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-p-tolylimidazo    [1,5-f][1,2,4]triazin-4(3H)-one (I-117);-   3-([4-Hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl]methyl)-7-(4-methylphenyl)-3H,4H-imidazo[4,3-f][1,2,4]triazin-4-one    (I-119);-   (S)-3-((1-(3-(1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(p-tolyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one    (I-120);-   (R)-3-((1-(3-(1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(p-tolyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one    (I-121);-   3-((1-(2-cyclopropyloxazole-5-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one    (I-122);-   3-((1-(4-(1H-pyrazol-1-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one    (I-123);-   7-(4-fluorophenyl)-3-((4-hydroxy-1-(4-methylbenzoyl)piperidin-4-yl)methyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one    (I-124); and-   3-((1-(3-fluoro-4-methylbenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one    (I-125).

In another embodiment of the invention, the compounds of Formula (I) areenantiomers. In some embodiments the compounds are the (S)-enantiomer.In other embodiments the compounds are the (R)-enantiomer. In yet otherembodiments, the compounds of Formula (I) may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Compounds of the invention, and pharmaceutically acceptable salts,hydrates, solvates, stereoisomers and prodrugs thereof may exist intheir tautomeric form (for example, as an amide or imino ether). Allsuch tautomeric forms are contemplated herein as part of the presentinvention.

The compounds of the invention may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of theinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention. Each compound herein disclosed includes all the enantiomersthat conform to the general structure of the compound. The compounds maybe in a racemic or enantiomerically pure form, or any other form interms of stereochemistry. The assay results may reflect the datacollected for the racemic form, the enantiomerically pure form, or anyother form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the invention may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the invention may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.)Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The compounds of Formula I may form salts which are also within thescope of this invention. Reference to a compound of the Formula hereinis understood to include reference to salts thereof, unless otherwiseindicated.

The present invention relates to compounds which are modulators of USP7.In one embodiment, the compounds of the present invention are inhibitorsof USP7.

The invention is directed to compounds as described herein andpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, and pharmaceutical compositionscomprising one or more compounds as described herein, orpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof.

Method of Synthesizing the Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of compounds ofFormula (I).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula (I). Accordingly, the present invention includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Compounds of thepresent invention can be synthesized by following the steps outlined inGeneral Schemes 1, 2, 3, and 4 which comprise different sequences ofassembling intermediates Ia-Iv. Starting materials are eithercommercially available or made by known procedures in the reportedliterature or as illustrated.

wherein R₂-R₇, X₁, m and n are defined as in Formula (I).

The general way of preparing target molecules of Formula I by usingintermediates Ia, Ib, Ic, Id, Ie, If, Ig, and Ih is outlined in GeneralScheme 1. Treatment of Ia with hydroxylamine-O-sulfonic acid and base,i.e., aqueous potassium hydroxide (KOH), in a solvent, i.e., water,provides intermediate Ib. Oxidation of Ib using a base, i.e., potassiumhydroxide (KOH), in a solvent, i.e., water, provides intermediate Ic.Intermediate Ie is then prepared by formylation of Ic with formic acid,sodium acetate and optionally a solvent to provide Id which thencyclizes to form the desired product. Alkylation of Ie with If in thepresence of a base, i.e., cesium carbonate, and a solvent, i.e., DMF atelevated temperature provides intermediate Ig. Deprotection ofintermediate Ig using a strong acid such as trifluoroacetic acid (TFA)in a solvent, i.e., dichloromethane (DCM) yields Ih. Acylation ofintermediate Ih to provide compounds of formula (I) where X₁ is C, canbe accomplished by coupling of an acid under standard couplingconditions using a coupling reagent, i.e.,[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF to provide compoundsof Formula (I). Alternatively, intermediate Ih can be acylated with anacid chloride or carbamoyl chloride using a base, i.e., triethylamine orDIPEA, and optionally in solvent. For synthesis of compounds of formulaI where X₁ is S or S(O), intermediate Ih can be treated with a sulfonylchloride or a sulfinic chloride and a base, i.e., triethylamine orN,N-diisopropylethylamine (DIPEA), in a solvent, i.e., dichloromethane,DMF to provide the desired product.

wherein R₁-R₆, X₁, m and n are defined as in Formula (I).

Alternatively, molecules of formula I can be prepared usingintermediates Ii, Ij, and Ik as outlined in General Scheme 2. Acylationof Ii can be accomplished by coupling of an acid under standard couplingconditions using a coupling reagent, i.e.,[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF. Alternatively,intermediate Ii, can be acylated with an acid chloride or carbamoylchloride using a base, i.e., triethylamine or DIPEA, and optionally insolvent to provide intermediate Ij. Deprotection of intermediate Ijusing a strong acid such as trifluoroacetic acid (TFA) in a solvent,i.e., dichloromethane (DCM) yields Ik. Acylation of intermediate Ik toprovide compounds of formula (I) where X₁ is C, can be accomplished bycoupling of an acid under standard coupling conditions using a couplingreagent, i.e.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidhexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF to provide compoundsof Formula (I). Alternatively, intermediate Ik can be acylated with anacid chloride or carbamoyl chloride using a base, i.e., triethylamine orDIPEA, and optionally in solvent. For synthesis of compounds of formulaI where X₁ is S or S(O), intermediate Ik can be treated with a sulfonylchloride or a sulfinic chloride and a base, i.e., triethylamine orN,N-diisopropylethylamine (DIPEA), in a solvent, i.e., dichloromethane,DMF to provide the desired product.

wherein R₂-R₆, X₁, m and n are defined as in Formula (I).

The general way of preparing target molecules of formula I by usingintermediates Il, If, Im, and In is outlined in General Scheme 3.Alkylation of II with If in the presence of a base, i.e., cesiumcarbonate, and a solvent, i.e., DMF at elevated temperature providesintermediate Im. Deprotection of intermediate Im using a strong acidsuch as trifluoroacetic acid (TFA) in a solvent, i.e., dichloromethane(DCM) yields In. Acylation of intermediate In to provide compounds offormula (I) where X₁ is C, can be accomplished by coupling of an acidunder standard coupling conditions using a coupling reagent, i.e.,[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF to provide compoundsof Formula (I). Alternatively, intermediate In can be acylated with anacid chloride or carbamoyl chloride using a base, i.e., triethylamine orDIPEA, and optionally in solvent. For synthesis of compounds of formulaI where X₁ is S or S(O), intermediate In can be treated with a sulfonylchloride or a sulfinic chloride and a base, i.e., triethylamine orN,N-diisopropylethylamine (DIPEA), in a solvent, i.e., dichloromethane,DMF to provide the desired product.

wherein R₁-R₆, X₁, m, and n are defined as in Formula (I).

The general way of preparing target molecules of formula I by usingintermediates Io, Ip, Iq, Ir, Is, It, Iu, and Iv is outlined in GeneralScheme 4. Cyclization of Io with 3,3-dibromo-1,1,1-trifluoropropan-2-oneusing sodium acetate in solvent, i.e., water, at elevated temperatureprovides intermediate Ip. Treatment of Ip with a base, i.e., sodiumhydroxide (NaOH), in a solvent, i.e., water, at elevated temperatureprovides intermediate Iq. Esterification of Iq in the presence ofthionyl chloride in a solvent, i.e., methanol, at elevated temperatureprovides intermediate Ir. Intermediate Is can be obtained by treatmentof Ir with a base, i.e., potassium tert-butoxide (KOtBu) and(Aminooxy)diphenylphosphine oxide in a solvent, i.e., dimethylformamide. Hydrolysis of Is in the presence of a base, i.e., lithiumhydroxide, in a solvent, i.e., tetrahydrofuran, water, providesIntermediate It. Amide Iv can be obtained by coupling of acid It withamine Iu under standard coupling conditions using a coupling reagent,i.e., [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF. Cyclization of Ivwith triethoxymethane optionally in a solvent at elevated temperatureprovides compounds of Formula (I).

It should be understood that in the description and formula shown above,the various groups R₁-R₇, X₁, m, n, and other variables are as definedabove, except where otherwise indicated. Furthermore, for syntheticpurposes, the compounds of General Schemes 1-4 are mere representativewith elected radicals to illustrate the general synthetic methodology ofthe compounds of Formula (I) as defined herein.

Methods of Using the Disclosed Compounds

Another aspect of the invention relates to a method of treating adisease or disorder associated with modulation of USP7. The methodcomprises administering to a patient in need of a treatment for diseasesor disorders associated with modulation of USP7 an effective amount thecompositions and compounds of Formula (I).

In another aspect, the present invention is directed to a method ofinhibiting USP7. The method involves administering to a patient in needthereof an effective amount of a compound of Formula (I).

Another aspect of the present invention relates to a method of treating,preventing, inhibiting or eliminating a disease or disorder in a patientassociated with the inhibition of USP7, the method comprisingadministering to a patient in need thereof an effective amount of acompound of Formula (I). In one embodiment, the disease or disorder isselected from the group consisting of cancer and metastasis,neurodegenerative diseases, immunological disorders, diabetes, bone andjoint diseases, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, viral infectivity and/or latency, and bacterial infections anddiseases.

The present invention also relates to the use of an inhibitor of USP7for the preparation of a medicament used in the treatment, prevention,inhibition or elimination of a disease or condition mediated by USP7,wherein the medicament comprises a compound of Formula (I).

In another aspect, the present invention relates to a method for themanufacture of a medicament for treating, preventing, inhibiting, oreliminating a disease or condition mediated by USP7, wherein themedicament comprises a compound of Formula (I).

Another aspect of the present invention relates to a compound of Formula(I) for use in the manufacture of a medicament for treating a diseaseassociated with inhibiting USP7.

In another aspect, the present invention relates to the use of acompound of Formula (I) in the treatment of a disease associated withinhibiting USP7.

Another aspect of the invention relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I).

In another aspect, the present invention relates to a method of treatinga neurodegenerative disease. The method comprises administering to apatient in need thereof an effective amount of a compound of Formula(I).

Another aspect of the invention relates to a method of treating a viralinfection and disease. The method comprises administering to a patientin need thereof an effective amount of a compound of Formula (I).

In another aspect, the present invention relates to a method of treatingan inflammatory disease or condition. The method comprises administeringto a patient in need thereof an effective amount of a compound ofFormula (I).

Another aspect of the invention relates to a method of inducing cellcycle arrest, apoptosis in tumor cells, and/or enhanced tumor-specific Tcell immunity. The method comprises contacting the cells with aneffective amount of a compound of Formula (I).

In one embodiment, the present invention relates to the use of aninhibitor of USP7 for the preparation of a medicament used in treatment,prevention, inhibition or elimination of a disease or disorderassociated with associated with cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases.

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of cancers including, but not limited to, liposarcoma,neuroblastoma, glioblastoma, bladder cancer, adrenocortical cancer,multiple myeloma, colorectal cancer, non-small cell lung cancer, HumanPapilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroidor vaginal cancer or Epstein-Barr Virus-associated nasopharyngealcarcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkinlymphoma or diffuse large B-cell lymphoma.

In some embodiments, the patient is selected for treatment based on geneamplification and/or elevated tumor expression of USP7, MDM2 or MDM4relative to tissue-matched expression. In other embodiments, the patientis selected for the treatment based on tumor expression of wild typeTP53 or based on the tumor immune cell composition, specificallyelevated regulatory T lymphocytes, CD4+CD25+FoxP3+ T cells.

In some embodiments, administration of a compound of Formula (I) or apharmaceutical composition comprising a compound of the presentinvention and a pharmaceutically acceptable carrier induces a change inthe cell cycle or cell viability.

For example, the change in the cell cycle or cell viability may beindicated by decreased tumor levels of MDM2 protein and/or increasedlevels of TP53, CDKN1A (p21, Cip1), PUMA or BAX or by increasedexpression of one or more p53 target genes. In one embodiment, the p53target genes include, but are not limited to, CDKN1A (p21, Cip1), BBC3(PUMA), BAX or MDM2.

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of neurodegenerative diseases including, but not limited to,Alzheimer's disease, multiple sclerosis, Huntington's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,amyotrophic lateral sclerosis, or encephalitis.

Another embodiment of the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of viral infections and diseases including but not limited to,herpes simplex-1 or -2 viral infections, hepatitis A, hepatitis C, SARScoronavirus infection and disease, Epstein-Barr virus, rhinoviralinfections and diseases, adenoviral infections and diseases, orpoliomyelitis.

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of inflammatory diseases or conditions is associated withmetabolic disorders including, but not limited to, Type II diabetes,insulin resistance cardiovascular disease, arrhythmia, atherosclerosis,coronary artery disease, hypertriglyceridemia, dyslipidemia,retinopathy, nephropathy, neuropathy, or macular edema.

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of inflammatory diseases or conditions is associated withinflammatory bowel diseases including, but not limited to, ileitis,ulcerative colitis, Barrett's syndrome, or Crohn's disease

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

In one embodiment, are provided methods of treating a disease ordisorder associated with modulation of USP7 including, cancer andmetastasis, neurodegenerative diseases, immunological disorders,diabetes, bone and joint diseases, osteoporosis, arthritis inflammatorydisorders, cardiovascular diseases, ischemic diseases, viral infectionsand diseases, viral infectivity and/or latency, and bacterial infectionsand diseases, comprising administering to a patient suffering from atleast one of said diseases or disorder a compound of Formula (I).

One therapeutic use of the compounds or compositions of the presentinvention which inhibit USP7 is to provide treatment to patients orsubjects suffering from cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases.

The disclosed compounds of the invention can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564 which ishereby incorporated by reference in its entirety.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoylresidues. Furthermore, the Disclosed compounds can be coupled to a classof biodegradable polymers useful in achieving controlled release of adrug, for example, polylactic acid, polyepsilon caprolactone,polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels. In one embodiment, disclosed compoundsare not covalently bound to a polymer, e.g., a polycarboxylic acidpolymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on either Bruker or Varian spectrometers at 300 or 400MHz. Spectra are given in ppm (δ) and coupling constants, J, arereported in Hertz. Tetramethylsilane (TMS) was used as an internalstandard. Mass spectra were collected using a Waters ZQ Single Quad MassSpectrometer (ion trap electrospray ionization (ESI)). Purity and lowresolution mass spectral data were measured using Waters Acquity i-classultra-performance liquid chromatography (UPLC) system with Acquity PhotoDiode Array Detector, Acquity Evaporative Light Scattering Detector(ELSD) and Waters ZQ Mass Spectrometer. Data was acquired using WatersMassLynx 4.1 software and purity characterized by UV wavelength 220 nm,evaporative light scattering detection (ELSD) and electrospray positiveion (ESI). (Column: Acquity UPLC BEH C18 1.7 μm 2.1×50 mm; Flow rate 0.6mL/min; Solvent A (95/5/0.1%: 10 mM Ammonium Formate/Acetonitrile/FormicAcid), Solvent B (95/5/0.09%: Acetonitrile/Water/Formic Acid); gradient:5-100% B from 0 to 2 mins, hold 100% B to 2.2 mins and 5% B at 2.21mins. Preparatory HPLC purifications were conducted on a Waters SunFireC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mm, Waters XBridge BEH C18OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm with UV detection (Waters 2489UV/998 PDA), Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×150mm, Waters XBridge BEH Shield RP18 OBD Prep Column, 130 Å, 5 μm, 19mm×150 mm, or Waters XSelect CSH C18 OBD Prep Column, 130 Å, 5 μm, 19mm×150 mm at 254 nm or 220 nm using a standard solvent gradient program(i.e., HPLC Methods 1-2 as designated below).

Preparative HPLC Polar Method 1 (ESI, 5.5 Min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.Conditions: Mobile phase A: water with 0.1% formic acid/Mobile phase Bacetonitrile with 0.1% formic acidColumn: Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mmColumn temperature: AmbientLC gradient: 15% for 0.9 min, then 15% to 25% in 0.01 min, then 25% to65% in 3.84 min; and 65% to 100% in 0.01 min; hold at 100% for 0.74 min.LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at columndilution UV wavelength: 220 nm and 254 nmIonization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Generic Method 2 (ESI, 5.5 Min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.Conditions: Mobile phase A: water with 0.1% ammonium hydroxide/Mobilephase B acetonitrile with 0.1% ammonium hydroxideColumn: Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mmColumn temperature: AmbientLC gradient: Hold 35% B for 0.9 min, then 35% to 45% in 0.01 min; then45% to 85% in 3.84 min; then 85 to 100% to 100% in 0.01 min; hold at100% for 0.74 min.LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at columndilution UV wavelength: 220 nm and 254 nmIonization Mode: Electrospray Ionization; positive/negative; ESI+Abbreviations used in the following examples and elsewhere herein are:

-   -   atm atmosphere    -   br broad    -   DBU 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine    -   DIPEA N,N-diisopropylethylamine    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   EDC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride    -   ESI electrospray ionization    -   h hour(s)    -   HATU        [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxide hexafluorophosphate    -   HPLC high-performance liquid chromatography    -   LCMS liquid chromatography-mass spectrometry    -   m multiplet    -   MHz megahertz    -   min minutes    -   MS molecular sieves    -   MW microwave    -   NMR nuclear magnetic resonance    -   ppm parts per million    -   TLC thin layer chromatography

Example 1: Intermediate 2-1. tert-Butyl4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carboxylate

To a 100-mL round-bottom flask fitted with a nitrogen inlet, magneticstir bar and condenser was charged cesium carbonate (21.7 g, 66.6 mmol),tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (6.16 g, 28.9mmol), pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (3.00 g, 22.2 mmol), andDMF (50 ml). The reaction was heated at 80° C. for 2 h and then dilutedwith water (50 mL) and ethyl acetate (100 mL). The organic phase wasremoved and the aqueous phase was further extracted with ethyl acetate(100 mL). The combined organic layers were concentrated under reducedpressure and the residue was purified by column chromatography using 1:1ethyl acetate/hexane as mobile phase to provide tert-butyl4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carboxylate(Intermediate 2-1, 4.62 g, 60%). LCMS (ESI) m/z 349.02 [M+H].

Example 2: Intermediate 2-2.3-((4-Hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt

To a 50-ml round-bottom flask fitted with a nitrogen inlet and magneticstir bar was added tert-butyl4-hydroxy-4-((4-oxopyrrolo[1,2-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carboxylate(Intermediate 2-1, 2.60 g, 7.46 mmol), dichloromethane (26 ml) andtrifluoroacetic acid (4.60 ml, 59.7 mmol). The reaction was stirred atroom temperature for 18 h and then concentrated under reduced pressure.Dichloromethane (2 mL) and hexane (30 mL) were added and the mixture wasstirred at room temperature for 3 h. The solids were removed byfiltration, washed with hexane (10 mL) and dried under reduced pressureto provide3-((4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt (Intermediate 2-2, 2.21 g, 81%). LCMS (ESI)m/z 249.06 [M+H]. ¹H NMR (400 MHz, DMSO-d⁶) δ 7.92 (s, 1H), 7.59 (dd,1H), 6.90 (dd, 1H), 6.55 (dd, 1H), 3.89 (s, 2H), 3.14 (br d, 2H),3.07-2.88 (m, 2H), 1.81-1.64 (m, 2H), 1.61-1.50 (m, 2H) ppm.

Example 3: Intermediate 2-3.3-((1-(2-Bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

To a 50-ml round-bottom flask fitted with a nitrogen inlet, magneticstir bar, and condenser was charged3-((4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt (Intermediate 2-2, 0.70 g, 1.93 mmol),2-bromobenzoic acid (0.43 g, 2.13 mmol), EDC (0.407 g, 2.125 mmol),1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.15 g, 0.97 mmol),1,2-dichloroethane (25 ml), and triethylamine (1.35 ml, 9.66 mmol). Thereaction mixture was heated at 50° C. for 0.4 h and then cooled to roomtemperature. Saturated aqueous sodium bicarbonate (20 ml) anddichloromethane (20 ml) were added and the phases were separated. Theorganic phase was washed with hydrochloric acid (1.0 M aqueous, 10 mL)and water (10 ml), then concentrated under reduced pressure. The residuewas dissolved in ethyl acetate (10 ml) and hexane was added until asolid precipitated. The slurry was stirred for 3 h, and then the solidswere filtered, washed with hexane (10 ml) and dried under reducedpressure to afford3-((1-(2-bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(Intermediate 2-3, 0.51 g, 61% yield). LCMS (ESI) m/z 431.96 [M+H]

Example 4: Intermediate 2-4.3-((1-(3-Bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

3-((1-(3-Bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(Intermediate 2-4) was prepared in 65% yield according to the procedureused for the preparation of3-((1-(2-bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(Intermediate 2-3). LCMS (ESI) m/z 431.97 [M+H].

Example 5: Intermediate 2-5.3-((1-(4-Bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

3-((1-(4-Bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(Intermediate 2-5) was prepared in 79% yield according to the procedureused for the preparation of3-((1-(2-bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(Intermediate 2-3). LCMS (ESI) m/z 431.86 [M+H].

Example 6: Intermediate 2-6. tert-Butyl4-((6-amino-4-oxopyrrolo[2,1-f][1,2,4]triazin

3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate

A 25-mL round-bottomed flask equipped with a magnetic stir bar wascharged with 6-aminopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one hydrochloride(1.25 g, 6.70 mmol), tert-butyl1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.57 g, 7.37 mmol), cesiumcarbonate (5.46 g, 16.8 mmol), and DMF (10 mL). The mixture was heatedat 80° C. for 24 h, then cooled to room temperature, diluted with water(20 mL) and extracted with dichloromethane (20 mL). The organic layerwas washed with sodium chloride (5% aqueous solution, 20 mL) and thenconcentrated under reduced pressure. The crude product was purified byflash chromatography on silica gel with acetonitrile then 10:1acetonitrile:ammonium hydroxide solution to afford tert-butyl4-((6-amino-4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate(Intermediate 2-6, 1.24 g, 51% yield). LCMS (ESI) m/z 386 [M+Na]. ¹H NMR(400 MHz, DMSO-d⁶) δ 7.72 (s, 1H), 6.87 (d, 1H), 6.20 (d, 1H), 4.84 (s,1H), 4.44 (s, 2H), 3.80 (br s, 2H), 3.62 (br d, 2H), 3.04 (br s, 2H),1.45-1.29 (m, 4H), 1.37 (s, 9H) ppm.

Example 7: Intermediate 2-7.7-Methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

Step 1. 5-Methyl-1H-pyrrole-2-carbaldehyde

DMF (8.54 g, 117 mmol) and dichloroethane (120 mL) were added to a250-mL 3-necked round-bottom flask fitted with a magnetic stir bar.Phosphoryl chloride (17.9 g, 117 mmol) was added dropwise with stirringat 0° C. The resulting solution was stirred for 15 min at roomtemperature and then 2-methyl-1H-pyrrole (10.0 g, 123 mmol) was addeddropwise with stirring at 0° C. The resulting solution was stirred at80° C. for 30 min. A solution of sodium acetate (46 g, 561 mmol) inwater (130 mL) was then added at room temperature. The resultingsolution was stirred for 20 min at 80° C. then cooled to roomtemperature and quenched with water (100 mL). The resulting solution wasextracted with dichloromethane (3×250 mL) and the organic layers werecombined and washed with saturate aqueous sodium bicarbonate solution(150 mL). The organic phase was dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/hexane (1:5 v/v) toafford 5-methyl-1H-pyrrole-2-carbaldehyde (7.50 g, 56%). LCMS (ESI) m/z110 [M+H].

Step 2. 1-Amino-5-methyl-1H-pyrrole-2-carbonitrile

5-Methyl-1H-pyrrole-2-carbaldehyde (Step 1, 4.50 g, 41.2 mmol), water(90 mL) and hydroxylamine-O-sulfonic acid (16.34 g, 144 mmol) were addedto a 250-mL round-bottom flask fitted with a magnetic stir bar. Asolution of potassium hydroxide (46.2 g, 824 mmol) in water (100 mL) wasadded dropwise with stirring at 0° C. over 1 h. The resulting mixturewas allowed to stir for 3.5 h at 0° C. and then for an additional 1 h atroom temperature. The mixture was filtered and extracted withdichloromethane (3×250 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography eluting withethyl acetate/petroleum ether (1:10 v/v) to afford1-amino-5-methyl-1H-pyrrole-2-carbonitrile (680 mg, 14%). LCMS (ESI) m/z122 [M+H].

Step 3. 1-Amino-5-methyl-1H-pyrrole-2-carboxamide

1-Amino-5-methyl-1H-pyrrole-2-carbonitrile (680 mg, 5.61 mmol), DMSO (5mL), sodium hydroxide (1.12 g, 28.0 mmol) and ethanol (20 mL) were addedto a 100-mL round-bottom flask fitted with a magnetic stir bar. This wasfollowed by the addition of hydrogen peroxide (30 wt % aqueous, 6.37 g)dropwise with stirring at 0° C. The resulting solution was stirred for 4h at room temperature, diluted with water (50 mL) and extracted withethyl acetate (3×250 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford 1-amino-5-methyl-1H-pyrrole-2-carboxamide which wasused in next step without further purification. LCMS (ESI) m/z 140[M+H].

Step 4. 1-Formamido-5-methyl-1H-pyrrole-2-carboxamide

1-Amino-5-methyl-1H-pyrrole-2-carboxamide (Step 3), formic acid (10 mL)and sodium acetate (340 mg) were added to a 50-mL round-bottom flaskfitted with a magnetic stir bar. The resulting solution was stirred for16 h at room temperature and then concentrated under reduced pressure.The residue was diluted with water (30 mL) and extracted withdichloromethane (3×50 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by column chromatography eluting with ethylacetate/petroleum ether (1:50 then 100:1 v/v) to afford1-formamido-5-methyl-1H-pyrrole-2-carboxamide (200 mg, 69% over twosteps). LCMS (ESI) m/z 168 [M+H].

Step 5. 7-Methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

1-Formamido-5-methyl-1H-pyrrole-2-carboxamide (200 mg, 1.20 mmol),methanol (20 mL) and sodium methoxide (220 mg, 4.07 mmol) were added toa 50-mL round-bottom flask fitted with a nitrogen inlet, magnetic stirbar and condenser. The resulting solution was stirred for 6 h at 80° C.and then concentrated under reduced pressure. The residue was dilutedwith water (30 mL) and extracted with ethyl acetate (3×40 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography with ethyl acetate to give7-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (Intermediate 2-7, 100mg, 56%). LCMS (ESI) m/z 150 [M+H].

Example 8: Intermediate 2-8.6-Methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

Step 1. Mixture of 3-methyl-1H-pyrrole-2-carbaldehyde and4-methyl-1H-pyrrole-2-carbaldehyde

DMF (2.1 mL, 27.1 mmol) and 1,2-dichloroethane (10 mL) were added to a100-mL 3-necked round-bottom flask fitted with a magnetic stir bar.Phosphoryl chloride (4.17 g, 27.2 mmol) was added dropwise with stirringat 0° C. The resulting solution was stirred for 15 min at roomtemperature. A solution of 3-methyl-1H-pyrrole (2.00 g, 24.7 mmol) in1,2-dichloroethane (2 mL) was added dropwise with stirring at 0° C. andthe resulting solution was stirred for 15 min at 80° C. A solution ofsodium acetate (10.8 g, 132 mmol) in water (30 mL) was added at roomtemperature and the resulting solution was stirred for 20 min at 100° C.The resulting mixture was extracted with dichloromethane (4×150 mL). Theorganic layers were combined, washed with saturated aqueous sodiumbicarbonate (150 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:10 v/v) toafford a mixture of 3-methyl-1H-pyrrole-2-carbaldehyde and4-methyl-1H-pyrrole-2-carbaldehyde (2.20 g, 82%). LCMS (ESI) m/z 110[M+H].

Step 2. Mixture of 1-amino-4-methyl-1H-pyrrole-2-carbonitrile and1-amino-3-methyl-1H-pyrrole-2-carbonitrile

A mixture of 3-methyl-1H-pyrrole-2-carbaldehyde and4-methyl-1H-pyrrole-2-carbaldehyde (Step 1, 2.50 g, 22.7 mmol), water(50 mL) and hydroxylamine-O-sulfonic acid (9.00 g, 79.6 mmol) were addedto a 250-mL round-bottom flask fitted with a magnetic stir bar. Asolution of potassium hydroxide (25.5 g, 455 mmol) in water (50 mL) wasadded dropwise with stirring at 0° C. over 1 h. The resulting mixturewas allowed to stir for 3.5 h at 0° C. and then for an additional 1 h atroom temperature. The mixture was filtered and extracted withdichloromethane (3×150 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography eluting withethyl acetate/petroleum ether (1:10 v/v) to afford a mixture of1-amino-4-methyl-1H-pyrrole-2-carbonitrile and1-amino-3-methyl-1H-pyrrole-2-carbonitrile (545 mg, 20%). LCMS (ESI) m/z122 [M+H].

Step 3. 1-Amino-4-methyl-1H-pyrrole-2-carboxamide

A mixture of 1-amino-4-methyl-1H-pyrrole-2-carbonitrile and1-amino-3-methyl-1H-pyrrole-2-carbonitrile (Step 2, 1.1 g, 9.09 mmol),potassium hydroxide (2.50 g, 44.6 mmol) and water (10 mL) were added toa 100-mL round-bottom flask fitted with a magnetic stir bar. Theresulting solution was stirred for 3 d at room temperature and thenextracted with ethyl acetate (4×50 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography elutingwith ethyl acetate to afford 1-amino-4-methyl-1H-pyrrole-2-carboxamide(0.13 g, 10%). LCMS (ESI) m/z 140 [M+H].

Step 4. 1-Formamido-4-methyl-1H-pyrrole-2-carboxamide

1-Amino-4-methyl-1H-pyrrole-2-carboxamide (Step 3, 280 mg, 2.01 mmol),formic acid (20 mL) and sodium acetate (400 mg, 4.88 mmol) were added toa 100-mL round-bottom flask fitted with a magnetic stir bar. Theresulting solution was stirred for 16 h at room temperature and thenconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:2 v/v) toafford 1-formamido-4-methyl-1H-pyrrole-2-carboxamide (90 mg, 27%). LCMS(ESI) m/z 168 [M+H].

Step 5. 6-Methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

1-Formamido-4-methyl-1H-pyrrole-2-carboxamide (Step 4, 38 mg, 0.226mmol), methanol (10 mL) and sodium methoxide (20 mg, 0.285 mmol) wereadded to a 50-mL round-bottom flask fitted with a magnetic stir bar andcondenser. The resulting solution was stirred for 4 h at 80° C. and thenconcentrated under reduced pressure. The residue was diluted with water(20 mL) and extracted with dichloromethane (3×40 mL). The organic layerswere combined, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified bypreparative TLC eluting with ethyl acetate/petroleum ether (2:1 v/v) toafford 6-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (Intermediate 2-8,23 mg, 68%). LCMS (ESI) m/z 150 [M+H].

Example 9: Intermediate 2-9.7-Phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

Step 1. Methyl 1-amino-1H-imidazole-5-carboxylate

Methyl 1H-imidazole-5-carboxylate (3.50 g, 27.8 mmol), potassiumtert-butoxide (3.40 g, 30.3 mmol) and DMF (50 mL) were added to a 250-mL3-necked round-bottom flask fitted with a magnetic stir bar andthermometer. (Aminooxy)diphenylphosphine oxide (8.40 g, 36.0 mmol) wasthen added in portions at 0° C. The resulting solution was stirred for16 h at room temperature, diluted with ethyl acetate (100 mL), filteredand concentrated under reduced pressure to afford methyl1-amino-1H-imidazole-5-carboxylate which was used in next step withoutfurther purification. LCMS: (ESI) m/z 142 [M+H].

Step 2. Imidazo[5,1-f][1,2,4]triazin-4(3H)-one

Methyl 1-amino-1H-imidazole-5-carboxylate (Step 1) and formamide (20 mL)were added to a 3-necked 100-mL round-bottom flask fitted with amagnetic stir bar, condenser and thermometer. The resulting solution wasstirred for 16 h at 140° C., then cooled to room temperature, dilutedwith water (50 mL) and extracted with ethyl acetate (5×30 mL). Theorganic layers were combined, washed with brine (30 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography eluting withethyl acetate/petroleum ether (1:10 v/v) to affordimidazo[5,1-f][1,2,4]triazin-4(3H)-one (190 mg, 20% over two steps).LCMS: (ESI) m/z 137 [M+H]

Step 3. 7-Bromoimidazo[5,1-f][1,2,4]triazin-4(3H)-one

Bromine (376 mg, 2.35 mmol) was added at 0° C. to a solution ofimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Step 2, 160 mg, 1.18 mmol) andDMF (15 mL) in a 100-mL round-bottom flask fitted with a magnetic stirbar. The resulting solution was stirred for 30 min at room temperature,quenched by the addition of water (20 mL), and extracted with ethylacetate (5×30 mL). The organic layers were combined, washed with brine(30 mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to afford7-bromoimidazo[5,1-f][1,2,4]triazin-4(3H)-one which was used in nextstep without further purification. LCMS: (ESI) m/z 215, 217 [M+H].

Step 4. 7-Phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

7-Bromoimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Step 3, 150 mg, 0.70mmol), phenylboronic acid (170 mg, 1.39 mmol), potassium carbonate (289mg, 2.09 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (57 mg, 70 μmol), 1,4-dioxane (5 mL) and water (0.5mL) were added to a 3-necked 25-mL round-bottom flask fitted with anitrogen inlet, magnetic stir bar, condenser and thermometer. Theresulting mixture was stirred for 8 h at 100° C., then filtered, dilutedwith water (20 mL) and extracted with ethyl acetate (5×20 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by preparative TLC eluting with methanol/dichloromethane (1:50v/v) to afford 7-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(Intermediate 2-9, 100 mg, 67%). LCMS: (ESI) m/z 213 [M+H].

Example 10: Intermediate 2-10.(4-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl) methanone

Trimethylsulfoxonium iodide (2.60 g, 11.8 mmol), sodium hydride (60% inmineral oil, 480 mg, 12.5 mmol) and dimethyl sulfoxide (15 mL) wereadded to a 100-mL round-bottom flask fitted with a nitrogen inlet andmagnetic stir bar. The resulting mixture was stirred for 30 min at roomtemperature. 1-(4-Fluorobenzoyl)piperidin-4-one (2.00 g, 9.04 mmol) wasadded and stirring was continued for an additional 4 h at roomtemperature. The reaction was quenched by the addition of water (30 mL)and extracted with dichloromethane (3×30 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate to afford(4-fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone (Intermediate2-10, 0.75 g, 40%). LCMS: (ESI) m/z 236 [M+H].

Example 11: Intermediate 2-11.(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)(4-fluoro phenyl)methanone

(4-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone (Intermediate2-10, 500 mg, 2.13 mmol), methanol (20 mL), and ammonia (7.0 M solutionin methanol, 5 mL) were added to a 100-mL sealed tube fitted with amagnetic stir bar. The resulting solution was stirred for 3 h at roomtemperature and then concentrated under reduced pressure to afford(4-(aminomethyl)-4-hydroxypiperidin-1-yl)(4-fluorophenyl)methanone(Intermediate 2-11) which was used without any purification. LCMS: (ESI)m/z 253 [M+H].

Example 12: Intermediate 2-12.7-(4-fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one

The title compound was prepared according to the procedure outlined inExample 26, Steps 1-3, utilizing1-amino-2-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid (Example 23,Step 5) as the starting material.

Example 13: Intermediate 2-13. 4-(1H-pyrazol-1-yl)benzoic acid

Step 1. 4-(1H-pyrazol-1-yl)benzonitrile

A 100-mL round-bottom flask was charged with 4-fluorobenzonitrile (2 g,16.51 mmol), cesium carbonate (16 g, 49.11 mmol), N,N-dimethylformamide(20 mL) and 1H-pyrazole (2.24 g, 32.90 mmol). The resulting solution wasrefluxed for 2 h. The solids were removed by filtration and the filtratewas concentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:4v/v) to afford 4-(1H-pyrazol-1-yl)benzonitrile as a yellow oil (1.3 g,47%). LCMS: (ESI) m/z 170 [M+H].

Step 2. 4-(1H-pyrazol-1-yl)benzoic acid

A 250-mL round-bottom flask was charged with4-(1H-pyrazol-1-yl)benzonitrile (Step 1, 2 g, 11.82 mmol), ethanol (40mL), water (40 mL) and sodium hydroxide (705 mg, 17.63 mmol,). Theresulting solution was stirred at 105° C. 16 h and then concentratedunder vacuum. The residue was diluted with water (30 mL) and extractedwith ethyl acetate (50 mL). The pH of the aqueous phase was adjusted to5 with hydrochloric acid (6.0 M). The solids were collected byfiltration, washed with water (10 mL) and dried in an oven to afford4-(1H-pyrazol-1-yl)benzoic acid as a light yellow solid (Intermediate2-13, 1 g, 45%). LCMS: (ESI) m/z 189 [M+H].

Methods for the Synthesis of Compounds of Formula (I) Method A Example14:3-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(I-1)

Step 1. tert-Butyl4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carboxylate

To a solution of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (11 mg, 0.08mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (21 mg,0.10 mmol) in DMF (0.4 mL) was added cesium carbonate (78 mg, 0.24mmol). The reaction mixture was stirred at 80° C. for 16 h. The reactionmixture was cooled to room temperature, diluted with ethyl acetate (500μL) and washed with water (500 μL). The organic layer was concentratedunder reduced pressure to provide tert-butyl4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carboxylate,which was used in the preparation of3-((4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt (Step 2) without any further purification.LCMS: (ESI) m/z 371.41 [M+Na].

Step 2.3-((4-Hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt

To a solution of tert-butyl4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carboxylate(Step 1, 28 mg, 0.08 mmol) in 1,2-dichloroethane (0.4 mL) was addedtrifluoroacetic acid (0.062 mL, 0.80 mmol). The reaction mixture wasstirred at 50° C. for 2 h and concentrated under reduced pressure toprovide3-((4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt, which was used in the preparation of3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(Step 3) without any further purification. LCMS: (ESI) m/z 249.24 [M+H].

Step 3.3-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(I-1)

To a solution of3-((4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt (Step 2, 20 mg, 0.08 mmol) in1,2-dichloroethane (0.4 mL) was added 3-phenylbutanoic acid (16 mg,0.096 mmol), DIPEA (0.070 mL, 0.4 mmol) and HATU (37 mg, 0.096 mmol).The reaction mixture was stirred at 50° C. for 16 h. The reactionmixture was cooled to room temperature, diluted with dichloromethane(500 μL) and washed with water (500 μL). The crude product was purifiedby preparative HPLC (basic, generic) to afford3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(I-1, 4 mg, 13%). LCMS (ESI) m/z 395.26 [M+H]

Method B Example 15:3-((4-Hydroxy-1-(4′-methoxy-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (I-8)

3-((1-(3-Bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(Intermediate 2-4, 0.2 M in 1,4-dioxane, 150 μL, 40 μmol),(4-methoxyphenyl)boronic acid (0.2 M in 1,4-dioxane, 225 μL, 60 μmol),sodium bicarbonate (1.0 M aqueous, 90 μL, 120 μmol) andbis(triphenylphosphine)palladium(II) dichloride (0.01 M DMF, 150 μL, 2μmol) were combined and heated at 80° C. under nitrogen for 16 h. Thereaction mixture was cooled to room temperature. Ethyl acetate (500 μL)and saturated aqueous sodium bicarbonate (1.0 M aqueous, 410 μL) wereadded. The organic phase was separated and the aqueous layer wasextracted with ethyl acetate (500 μL). The combined organic phases wereconcentrated and purified by preparative HPLC (basic, generic) to afford3-((4-hydroxy-1-(4′-methoxy-[1,1′-biphenyl]-3-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(I-8, 6.8 mg, 37%). LCMS: (ESI) m/z 459.21 [M+H].

Method C Example 16:3-((4-Hydroxy-1-(2-phenyloxazole-5-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (I-32)

Step 1.3-((4-Hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt

To a solution of tert-butyl4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl) methyl)piperidine-1-carboxylate (Intermediate 2-1, 0.014 mg, 0.04 mmol) in1,2-dichloroethane (0.2 mL) was added trifluoroacetic acid (0.2 mL, 2.58mmol). The reaction mixture was stirred at 50° C. for 2 h andconcentrated to provide3-((4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt, which was used without any furtherpurification. LCMS: (ESI) m/z 249 [M+H].

Step 2.3-((4-Hydroxy-1-(2-phenyloxazole-5-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1f][1,2,4]triazin-4(3H)-one(I-32)

To3-((4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt (Step 1; 15 mg, 0.04 mmol) was added2-phenyloxazole-5-carboxylic acid (0.2 M in 1,2-dichloroethane, 0.24 mL,0.048 mmol), DIPEA (0.035 mL, 0.2 mmol) and HATU (0.4 M in acetonitrile,0.12 mL, 0.048 mmol). The reaction mixture was stirred at 50° C. for 16h and then cooled to room temperature. The solution was diluted withdichloromethane and washed with water. The crude product was purified bypreparative HPLC (basic, generic) to afford3-((4-hydroxy-1-(2-phenyloxazole-5-carbonyl)piperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(I-32, 8.7 mg, 52%). LCMS (ESI) m/z 420.15 [M+H].

Method D Example 17:3-((1-(3-Chloro-4′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(I-51)

Step 1.3-((1-(4-Bromo-2-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

To3-((4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt (Intermediate 2-1, Method C, Step 1; 15 mg,0.04 mmol) was added 4-bromo-2-chlorobenzoic acid (0.2 M in 1,4-dioxane,0.24 mL, 0.048 mmol), DIPEA (0.035 mL, 0.2 mmol) and HATU (0.2 M inacetonitrile, 0.24 mL, 0.048 mmol). The reaction mixture was stirred at50° C. for 16 h and then concentrated under reduced pressure. Ethylacetate (600 μL) and saturated aqueous sodium bicarbonate (600 μL) wereadded. The phases were separated and the aqueous phase was furtherextracted with ethyl acetate (600 μL). The combined organic extractswere concentrated under reduced pressure to afford3-((1-(4-bromo-2-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onewhich was used without further purification.

Step 2.3-((1-(3-Chloro-4′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(I-51)

(4-(pyrrolidine-1-carbonyl)phenyl)boronic acid (0.2 M in 1,4-dioxane,0.4 mL, 80 μmol), tribasic potassium phosphate (1.0 M aqueous, 0.2 mL,200 μmol) and tetrakis[triphenylphosphine]palladium(0) (0.01 M intoluene, 80 μL, 4 μmol) were added to a solution of3-((1-(4-bromo-2-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(Step 1) in 1,4-dioxane (200 μL). The resulting mixture was heated at80° C. under nitrogen for 16 h and then concentrated under reducedpressure. Ethyl acetate (0.6 mL) and saturated aqueous sodiumbicarbonate (0.6 mL) were added. The phases were separated and theaqueous phase was further extracted with ethyl acetate (0.6 mL). Thecombined organic extracts were concentrated under reduced pressure andthe residue was purified by preparative HPLC (basic, generic) to afford3-((1-(3-chloro-4′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(I-51) 4.2 mg, 19%). LCMS: (ESI) m/z 560.29 [M+H].

Method E Example 18:N-(3-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-phenylthiazole-4-carboxamide(I-112)

Step 1. tert-Butyl4-hydroxy-4-((4-oxo-6-(2-phenylthiazole-4-carboxamido)pyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carboxylate*

2-Phenylthiazole-4-carboxylic acid (0.2 M in 1,4-dioxane, 240 μL, 48μmol), DIPEA (15 μL, 86 μmol) and HATU* (0.4 M acetonitrile, 110 μL, 86μmol) were added to a solution of tert-butyl4-((6-amino-4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate(Intermediate 2-6, 15 mg, 40 μmol) in 1,2-dichloroethane (200 μL). Thereaction mixture was heated at 50° C. for 16 h then cooled to roomtemperature. Ethyl acetate (0.6 mL) and saturated aqueous sodiumbicarbonate (0.6 mL) were added. The phases were separated and theaqueous phase was further extracted with ethyl acetate (0.6 mL). Thecombined organic extracts were concentrated under reduced pressure toafford tert-butyl4-hydroxy-4-((4-oxo-6-(2-phenylthiazole-4-carboxamido)pyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carboxylate which was used without further purification orcharacterization. *Neat acid chlorides (1.2 eq) were also used in placeof carboxylic acids and HATU.

Step 2. N-(3-((4-Hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-phenylthiazole-4-carboxamidetrifluoroacetic acid salt

Trifluoroacetic acid (62 μL, 800 μmol) was added to a solution oftert-butyl4-hydroxy-4-((4-oxo-6-(2-phenylthiazole-4-carboxamido)pyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carboxylate (Step 1) in 1,2-dichloroethane (200 μL). Theresulting mixture was heated at 50° C. for 2 h and then concentratedunder reduced pressure. 1,2-Dichloroethane (200 μL) was added and theresulting mixture was stirred at room temperature for 15 min thenconcentrated under reduced pressure to affordN-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-phenylthiazole-4-carboxamidetrifluoroacetic acid salt which was used without further purification orcharacterization.

Step 3.N-(3-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-phenylthiazole-4-carboxamide(I-112)

Cyclopropanecarbonyl chloride (0.2 M in 1,2-dichloroethane, 240 μL, 48μmol) and DIPEA (35 μL, 200 μmol) were added to a solution ofN-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-phenylthiazole-4-carboxamidetrifluoroacetic acid salt (Step 2) in 1,2-dichloroethane (200 μL). Thereaction mixture was heated at 50° C. for 16 h, cooled to roomtemperature and concentrated under reduced pressure. The crude productwas purified by preparative HPLC (acidic, polar) to affordN-(3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-2-phenylthiazole-4-carboxamide(I-112, 5.6 mg, 27% over three steps). LCMS: (ESI) m/z 519.18 [M+H].

Method F Example 19:1-(3-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(3-fluoro-2-methylphenyl)urea(I-97)

Step 1. tert-Butyl4-((6-(3-(3-fluoro-2-methylphenyl)ureido)-4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate

1-Fluoro-3-isocyanato-2-methylbenzene* (0.2 M in dichloroethane, 240 μL,48 μmol) and DIPEA (15 μL, 86 μmol) were added to a solution oftert-butyl4-((6-amino-4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate(Intermediate 2-6, 15 mg, 40 μmol) in 1,2-dichloroethane (200 μL) Thereaction mixture was heated at 50° C. for 4 h then concentrated underreduced pressure to afford tert-butyl4-((6-(3-(3-fluoro-2-methylphenyl)ureido)-4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylatewhich was used without further purification or characterization. *Neatcarbamoyl chlorides (1.2 eq) were also used in place of isocyanates

Step 2.1-(3-Fluoro-2-methylphenyl)-3-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)ureatrifluoroacetic acid

1-(3-Fluoro-2-methylphenyl)-3-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)ureatrifluoroacetic acid was prepared from tert-butyl4-((6-(3-(3-fluoro-2-methylphenyl)ureido)-4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate(Step 1) according to the procedure described in Method E, Step 2.

Step 3.1-(3-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(3-fluoro-2-methylphenyl)urea(I-97)

1-(3-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-(3-fluoro-2-methylphenyl)urea(I-97, 6.0 mg, 31% over three steps) was prepared from1-(3-fluoro-2-methylphenyl)-3-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)ureatrifluoroacetic acid (Step 2) according to the procedure described inMethod E, Step 3. LCMS: (ESI) m/z 483.24 [M+H]

Method G Example 20:N-(4′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-2-yl)methacrylamide (I-114)

Step 1.3-((1-(2′-Amino-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrole[2,1-f][1,2,4]triazin-4(3H)-one

3-((4-Hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt (Intermediate 2-2, 448 mg, 1.24 mmol), HATU(589 mg, 1.55 mmol), DIPEA (0.5 mL, 2.87 mmol),2′-amino-[1,1′-biphenyl]-4-carboxylic acid (213 mg, 1.00 mmol) anddichloromethane (30 mL) were added to a 500-mL round-bottom flask fittedwith a magnetic stir bar. The resulting solution was stirred for 2 h atroom temperature and then quenched with water (40 mL). The resultingsolution was extracted with dichloromethane (5×50 mL). The organiclayers were combined, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with dichloromethane/methanol (30:1 v/v) toafford3-((1-(2′-amino-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(220 mg, 50%). LCMS: (ESI) m/z 444 [M+H]

Step 2.N-(4′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-2-yl)methacrylamide(I-114)

3-((1-(2′-Amino-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (Step 1, 60 mg, 0.14 mmol),dichloromethane (10 mL) and triethylamine (57 mg, 0.56 mmol) were addedto a 100-mL round-bottom flask fitted with a magnetic stir bar andthermometer. A solution of 2-methylprop-2-enoyl chloride (14 mg, 0.14mmol) in dichloromethane (10 mL) was added dropwise at 0° C. Theresulting solution was stirred for 30 min at this temperature and thenquenched by the addition of water (10 mL). The resulting solution wasextracted with dichloromethane (5×20 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purified by preparativeHPLC* to affordN-(4′-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-2-yl)methacrylamide(I-114, 4.5 mg, 7%). LCMS: (ESI) m/z 512.34 [M+H]. ¹H NMR (300 MHz,CDCl₃) δ 8.37-8.34 (d, 1H), 7.54-7.52 (d, 4H), 7.46-7.39 (m, 4H),7.26-7.08 (m, 2H), 7.06-7.08 (d, 1H), 6.59-6.57 (t, 1H), 5.53 (s, 1H),5.32 (s, 1H), 4.47 (s, 1H), 4.10-3.92 (m, 2H), 3.66-3.40 (m, 3H), 3.1(s, 1H), 1.88 (s, 3H), 1.75-1.59 (m, 4H) ppm. *Column: Waters XBridgeBEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×150 mm. Mobile phase A:0.05% aqueous ammonium bicarbonate/Mobile phase B: acetonitrile.Gradient: 10% B to 67% B over 7 min. Detector: 220 and 254 nm.

Method H Example 21:4-(4-(4-Hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)piperazin-1-yl)benzonitrile (I-73)

Step 1.3-((4-Hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onehydrochloric acid salt

Hydrochloric acid (4.0 M in dioxane, 75 μL, 300 μmol) was added to asolution of tert-butyl4-hydroxy-4-((4-oxopyrrolo[1,2-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carboxylate(Intermediate 2-1, 10.5 mg, 30 μmol) in dichloromethane (150 μL). Theresulting mixture was heated at 50° C. for 2 h and then concentratedunder reduced pressure to afford3-((4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onehydrochloric acid salt which was used without further purification.LCMS: (ESI) m/z 249.05 [M+H].

Step 2.4-(4-(4-Hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)piperazin-1-yl)benzonitrile(I-73)

A solution of triphosgene (3.3 mg, 11.1 μmol) in dichloromethane (56 μL)was added to a solution of3-((4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onehydrochloric acid salt (Step 1) and DIPEA (25 μL, 144 μmol) indichloromethane (56 μL) and the resulting mixture was stirred for 1 minat room temperature. A solution of 4-(piperazin-1-yl)benzonitrile (6.2mg, 33 μmol) in dichloromethane (165 μL) was added and the resultingmixture was stirred for 75 min at room temperature and the concentratedunder reduced pressure. Saturated aqueous sodium bicarbonate (600 μL)was added and the mixture was extracted with ethyl acetate (2×600 μL).The combined organic extracts were concentrated under reduced pressureand the residue was purified by preparative HPLC (basic, generic) toafford4-(4-(4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carbonyl)piperazin-1-yl)benzonitrile(I-73, 1.7 mg, 13%). LCMS: (ESI) m/z 462.26 [M+H].

Method I Example 22:3-((1-(2-Chloro-4-(piperidin-1-ylmethyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (I-75)

Step 1.3-((1-(4-Bromo-2-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

A solution of HBTU (12.5 mg, 33 μmol) in acetonitrile (165 μL) was addedto a solution of3-((4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onetrifluoroacetic acid salt (Intermediate 2-2, 8 mg, 30 μmol),4-bromo-2-chlorobenzoic acid (8 mg, 32 μmol) and DIPEA (15 μL, 86 μmol)in 1,4-dioxane (308 μL). The reaction mixture was stirred at roomtemperature for 2 h, diluted with sodium hydroxide (1.0 M aqueous, 500μL) and extracted with ethyl acetate (2×500 μL). The combined organicextracts were concentrated under reduced pressure to afford3-((1-(4-bromo-2-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-onewhich was used without further purification. LCMS: (ESI) m/z 464.93[M+H].

Step 2.3-((1-(2-Chloro-4-(piperidin-1-ylmethyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

Potassium (bromomethyl)trifluoroborate (12 mg, 60 μmol), piperidine (59μL, 60 mol), water (30 μL) and 1,4-dioxane (570 μL) were combined, andheated at 80° C. with stirring for 16 h. The reaction mixture was cooledto room temperature. Solutions of3-((1-(4-bromo-2-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(Step 1) in 1,4-dioxane (150 μL), cesium carbonate (33 mg, 100 μmol) inmethanol (100 μL),dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphane(0.2 mg, 0.3 mol) in 1,4-dioxane (15 μL) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2 mg, 0.3 μmol) in 1,4-dioxane (15 μL) were added and the resultingmixture was stirred under nitrogen at 80° C. for 16 h. The mixture wasconcentrated under reduced pressure, diluted with sodium hydroxide (1.0M aqueous, 500 μL) and extracted with 3:1 ethyl acetate:acetonitrile(2×500 μL). The organic extracts were filtered through a UCTbenzenesulfonic acid-silica column (part number CUBCX15R3) eluting withammonia (2.0 M in methanol) and concentrated under reduced pressure. Theresidue was purified by preparative HPLC (basic, generic) to afford3-((1-(2-chloro-4-(piperidin-1-ylmethyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one(I-75, 1.4 mg, 10%). LCMS: (ESI) m/z 483.27 [M+H].

Method J Example 23:3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (I-116)

Step 1. 2-(4-Fluorophenyl)-5-(trifluoromethyl)-1H-imidazole

3,3-Dibromo-1,1,1-trifluoropropan-2-one (8.00 g, 29.7 mmol), sodiumacetate (4.90 g, 59.7 mmol) and water (20 mL) were added to a 3-necked250-mL round-bottom flask fitted with a nitrogen inlet, magnetic stirbar and thermometer. The resulting mixture was stirred for 30 min at100° C. and then cooled to room temperature. 4-Fluorobenzaldehyde (3.34g, 27.0 mmol), ammonium hydroxide (28 mL) and methanol (30 mL) wereadded. The resulting solution was stirred for 4 h at room temperatureand then extracted with ethyl acetate (3×50 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:1 v/v) toafford 2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-imidazole (2.80 g,45%). LCMS: (ESI) m/z 231 [M+H].

Step 2. 2-(4-Fluorophenyl)-1H-imidazole-5-carboxylic acid

2-(4-Fluorophenyl)-5-(trifluoromethyl)-1H-imidazole (Step 1, 1.40 g,6.08 mmol), water (30 mL), and sodium hydroxide (1.20 g, 30.0 mmol) wereadded to a 3-necked 100-mL round-bottom flask fitted with a magneticstir bar, condenser and thermometer. The resulting solution was stirredfor 16 h at 100° C., then cooled to room temperature and extracted withethyl acetate (3×20 mL). The aqueous layers were combined and acidifiedto ˜pH 6-7 with concentrated hydrogen chloride (35% aqueous). The solidswere collected by filtration and washed with hexane (3×20 mL) to afford2-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid (450 mg, 36%) whichwas used in the next step without further purification. LCMS: (ESI) m/z205 [M−H].

Step 3. Methyl 2-(4-fluorophenyl)-1H-imidazole-5-carboxylate

2-(4-Fluorophenyl)-1H-imidazole-5-carboxylic acid (Step 2, 300 mg, 1.46mmol), thionyl chloride (2 mL, 27.4 mmol) and methanol (15 mL) wereadded to a 3-necked 100-mL round-bottom flask fitted with a magneticstir bar, condenser and thermometer. The resulting solution was stirredfor 3 h at 65° C., then cooled to room temperature and concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:1 v/v) toafford methyl 2-(4-fluorophenyl)-1H-imidazole-5-carboxylate (200 mg,62%). LCMS: (ESI) m/z 221 [M+H].

Step 4. Methyl 1-amino-2-(4-fluorophenyl)-1H-imidazole-5-carboxylate

Methyl 2-(4-fluorophenyl)-1H-imidazole-5-carboxylate (Step 3, 200 mg,0.91 mmol), potassium tert-butoxide (255 mg, 2.27 mmol), and DMF (10 mL)were added to a 3-necked 100-mL round-bottom flask fitted with amagnetic stir bar and thermometer. The resulting solution was stirredfor 1 h at 0° C. (Aminooxy)diphenylphosphine oxide (318 mg, 1.36 mmol)was added and the resulting solution was stirred for 16 h at roomtemperature. The mixture was diluted with water (100 mL) and extractedwith ethyl acetate (3×100 mL). The organic layers were combined, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography eluting withdichloromethane/methanol (10:1 v/v) to afford methyl1-amino-2-(4-fluorophenyl)-1H-imidazole-5-carboxylate (120 mg, 56%).LCMS: (ESI) m/z 236 [M+H].

Step 5. 1-Amino-2-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid

Methyl 1-amino-2-(4-fluorophenyl)-1H-imidazole-5-carboxylate (Step 4,120 mg, 0.51 mmol), tetrahydrofuran (10 mL), water (2 mL) and lithiumhydroxide (18 mg, 0.75 mmol) were added to a 100-mL round-bottom flaskfitted with a magnetic stir bar. The resulting solution was stirred for3 h at room temperature. The pH value of the solution was adjusted to7-8 with hydrogen chloride (10% aqueous). The reaction mixture wasextracted with dichloromethane (4×40 mL) and the organic layers werecombined, dried over anhydrous sodium sulfate and concentrated underreduced pressure to afford1-amino-2-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid which was usedwithout further purification. LCMS: (ESI) m/z 220 [M−H].

Step 6.1-Amino-N-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-2-(4-fluorophenyl)-1H-imidazole-5-carboxamide

1-Amino-2-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid (Step 5), HATU(232 mg, 0.61 mmol), DIPEA (158 mg), DMF (5 mL) and(4-(aminomethyl)-4-hydroxypiperidin-1-yl)(4-fluorophenyl)methanone(Intermediate 2-11, 123 mg, 0.49 mmol) were added to a 100-mLround-bottom flask fitted with a magnetic stir bar. The resultingsolution was stirred for 1 h at room temperature, diluted with water (50mL) and extracted with ethyl acetate (3×50 mL). The organic layers werecombined, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with ethyl acetate/petroleum ether (1:2 v/v) to afford1-amino-N-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-2-(4-fluorophenyl)-1H-imidazole-5-carboxamide(120 mg, 65%). LCMS: (ESI) m/z 456 [M+H].

Step 7.3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (I-116)

3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (Step 6, 120 mg, 0.26 mmol) andtriethoxymethane (10 mL) were added to a 3-necked 100-mL round-bottomflask fitted with a magnetic stir bar, thermometer and condenser. Theresulting solution was stirred for 16 h at 110° C. and then concentratedunder reduced pressure. The residue was first purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:2 v/v) andthen further purified by preparative HPLC* to afford3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (I-116, 14 mg, 11%). N LCMS:(ESI) m/z 466.26 [M+H]. ¹H NMR (400 MHz, DMSO-d⁶) δ 8.38-8.35 (m, 2H),8.09 (s, 1H), 7.94 (s, 1H), 7.48-7.38 (m, 4H), 7.29-7.25 (m, 2H), 5.00(s, 1H), 4.31-4.11 (m, 1H), 3.94 (s, 2H), 3.49-3.35 (m, 1H), 3.28-3.05(m, 2H), 1.68-1.31 (m, 4H) ppm. *Column: Waters XBridge BEH Shield RP18OBD Prep Column, 130 Å, 5 μm, 19 mm×150 mm. Mobile phase A: 0.05%aqueous ammonium bicarbonate/Mobile phase B: acetonitrile. Gradient: 5%B to 66% B over 10 min. Flow rate: 33 mL/min. Detector: 220 and 254 nm.

Example 24:3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-7-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(I-115)

3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-7-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(I-115) was synthesized according to Method A from Intermediate 2-9.LCMS: (ESI) m/z 466 [M+H].

Method K Example 25:3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-p-tolylimidazo[1,5-f][1,2,4]triazin-4 (3H)-one (I-117)

Step 1. 2-p-tolyl-5-(trifluoromethyl)-1H-imidazole

A 250-mL 3-necked round-bottom fitted with a magnetic stir bar, acondenser and a thermometer was charged with sodium acetate trihydrate(4.9 g) and water (20 mL) followed the addition of3,3-dibromo-1,1,1-trifluoropropan-2-one (8 g, 29.7 mmol). The reactionmixture was stirred for 30 min at 100° C. in an oil bath and then cooledto room temperature. A solution of 4-methylbenzaldehyde (3.4 g, 28.3mmol) and ammonium hydroxide (30 mL) in methanol (30 mL) was added atroom temperature. After stirring for 4 h, the reaction was quenched withwater (80 mL). The product was extracted with dichloromethane (3×60 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography eluting with 1:1 ethyl acetate/petroleum ether(1:1 v/v) to yield 2-p-tolyl-5-(trifluoromethyl)-1H-imidazole (2.2 g,34%) as a white solid. LCMS (ESI) m/z 227 [M+H].

Step 2. 2-p-tolyl-1H-imidazole-5-carboxylic acid

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar, acondenser and a thermometer was charged with2-p-tolyl-5-(trifluoromethyl)-1H-imidazole (2.2 g, 9.73 mmol), water (30mL), sodium hydroxide (2 g, 50.0 mmol). The solution was stirred for 16h at 100° C. in an oil bath and cooled to room temperature. The pH wasadjusted to 3 with hydrochloric acid (6N). The solids were collected byfiltration and dried in an oven to afford2-p-tolyl-1H-imidazole-5-carboxylic acid (1.5 g, 76%) as a white solidused without further purification. LCMS (ESI) m/z 203 [M+H].

Step 3. methyl 2-p-tolyl-1H-imidazole-5-carboxylate

A 100-mL round-bottom flask fitted with a magnetic stir bar was chargedwith 2-p-tolyl-1H-imidazole-5-carboxylic acid (1.5 g, 7.42 mmol),methanol (40 mL), sulfuroyl dichloride (8 mL). The solution was stirredfor 3 h at 70° C. in an oil bath and cooled to room temperature. Theresulting mixture was concentrated under vacuum to afford methyl2-p-tolyl-1H-imidazole-5-carboxylate (1.7 g, >95%) as a white solid usedwithout further purification. LCMS (ESI) m/z 217 [M+H].

Step 4. methyl 1-amino-2-p-tolyl-1H-imidazole-5-carboxylate

A 100-mL, 3-necked round-bottom flask fitted with a nitrogen inlet, amagnetic stir bar, a condenser and a thermometer was charged with methyl2-p-tolyl-1H-imidazole-5-carboxylate (1.7 g, 7.86 mmol),N,N-dimethylformamide (30 mL) and potassium tert-butanolate (1 g, 8.9mmol). The resulting solution was stirred for 1 h at 0° C. in awater/ice bath. To the reaction was slowly added aminodiphenylphosphinate (1.9 g, 8.15 mmol) in N,N-dimethylformamide (5 mL)with stirring at over 15 min. The reaction was warmed to 23° C. andstirred for 16 h before quenching with water (30 mL). The product wasextracted with dichloromethane (3×70 mL). The combined organic layer wasdried over Na₂SO₄, filtered and concentrated under vacuum to affordmethyl 1-amino-2-p-tolyl-1H-imidazole-5-carboxylate (2 g, >95%) as awhite solid used without further purification. LCMS (ESI) m/z 232 [M+H].

Step 5. 1-amino-2-p-tolyl-1H-imidazole-5-carboxylic acid

A 100-mL round-bottom flask fitted with a magnetic stir bar was chargedwith methyl 1-amino-2-p-tolyl-1H-imidazole-5-carboxylate (2 g, 8.65mmol), methanol (30 mL), and a solution of lithium hydroxide (500 mg,20.88 mmol) in water (20 mL). The solution was stirred for 4 h at roomtemperature and concentrated under vacuum. The pH was adjusted to 6 withhydrochloric acid (3N). The solids were collected by filtration anddried in an oven to afford 1-amino-2-p-tolyl-1H-imidazole-5-carboxylicacid (2.3 g, >95%) as a white solid used without further purification.LCMS (ESI) m/z 218 [M+H].

Step 6.1-amino-N-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-2-p-tolyl-1H-imidazole-5-carboxamide

A 100-mL round-bottom flask fitted with a nitrogen inlet was chargedwith 1-amino-2-p-tolyl-1H-imidazole-5-carboxylic acid (50 mg, 0.23mmol), N,N-dimethylformamide (4 mL),2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (130 mg, 0.34 mmol),4-(aminomethyl)-1-[(4-fluorophenyl)carbonyl]piperidin-4-ol (70 mg, 0.28mmol), ethyldiisopropylamine (90 mg, 0.70 mmol). The solution wasstirred for 1 h at room temperature and quenched with water (20 mL). Theproduct was extracted with ethyl acetate (3×25 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under vacuum toafford1-amino-N-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-2-p-tolyl-1H-imidazole-5-carboxamide(95 mg) as white solid which was used in next step without furtherpurification. LCMS (ESI) m/z 452 [M+H].

Step 7.3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-p-tolylimidazo[1,5-f][1,2,4]triazin-4(3H)-one (I-117)

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with1-amino-N-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-2-p-tolyl-1H-imidazole-5-carboxamide(95 mg, 0.21 mmol), formic acid (10 mL). The resulting solution wasstirred for 2 h at 100° C. in an oil bath and allowed cooled to 23° C.The reaction was quenched with water (60 mL) and the product wasextracted with ethyl acetate (3×25 mL). The combined organic layer wasdried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by preparatory HPLC* to afford3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-p-tolylimidazo[1,5-f][1,2,4]triazin-4(3H)-one (I-117, 17.4 mg, 18%) as a white solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 1.35-1.69 (m, 4H), 2.38 (s, 3H), 3.08-3.29 (m, 2H), 3.38-3.46(m, 1H), 3.93 (s, 2H), 4.15-4.27 (m, 1H), 5.00 (brs, 1H), 7.25-7.29 (m,2H), 7.36 (d, J=8.0 Hz, 2H), 7.45-7.48 (m, 2H), 7.92 (s, 1H), 8.07 (s,1H), 8.21 (d, J=8.4 Hz, 2H). LCMS (ESI) m/z 462 [M+H]. *Column: SunFirePrep C18, 19×150 mm. Mobile phase A: 0.05% aqueous ammoniumcarbonate/Mobile phase B: acetonitrile. Gradient: 10% B to 48% B over 8min. Detector: 220 and 254 nm.

Method L Example 26:3-([4-Hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl]methyl)-7-(4-methylphenyl)-3H,4H-imidazo[4,3-f][1,2,4]triazin-4-one(I-119)

Step 1. tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate

A 100-mL sealed tube fitted with a magnetic stir bar was charged withtert-Butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (300 mg, 1.28 mmol)and a solution of ammonium hydroxide in methanol (20 mL, 7M). Thesolution was stirred for 16 h at 80° C. in an oil bath and cooled toroom temperature. The mixture was concentrated under vacuum to affordtert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (350mg, >95%) used without further purification. LCMS (ESI) m/z 231 [M+H].

Step 2.4-([[1-Amino-2-(4-fluorophenyl)-1H-imidazol-5-yl]formamido]methyl)-4-hydroxypiperidine-1-carboxylate

A 100-mL round-bottom flask fitted with a magnetic stir bar was chargedwith 1-amino-2-p-tolyl-1H-imidazole-5-carboxylic acid (100 mg, 0.45mmol, 1.00 equiv),2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (262 mg, 0.69 mmol), ethyldiisopropylamine (178 mg,1.38 mmol), N,N-dimethylformamide (10 mL), tert-butyl4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (127 mg, 0.55 mmol).The solution was stirred for 1 h at room temperature and quenched withwater (30 mL). The product was extracted with ethyl acetate (3×30 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (1:4v/v) to afford tert-butyl4-([[1-amino-2-(4-fluorophenyl)-1H-imidazol-5-yl]formamido]methyl)-4-hydroxypiperidine-1-carboxylate(150 mg, 77%) as a light yellow oil. LCMS (ESI) m/z 430 [M+H].

Step 3.1-amino-N-[(4-hydroxypiperidin-4-yl)methyl]-2-(4-methylphenyl)-1H-imidazole-5-carboxamide(Intermediate 2-119)

A 100-mL 3 necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with tert-butyl4-([[1-amino-2-(4-methylphenyl)-1H-imidazol-5-yl]formamido]methyl)-4-hydroxypiperidine-1-carboxylate(150 mg, 0.35 mmol) and formic acid (10 mL). The solution was stirredfor 3 h at 100° C. in an oil bath and cooled to room temperature. Thereaction was diluted with water (10 mL) and the pH was adjusted to 7-8with aqueous sodium bicarbonate. The product was extracted with ethylacetate (3×15 mL). The combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with methanol/dichloromethane(1:9 v/v) to afford1-amino-N-[(4-hydroxypiperidin-4-yl)methyl]-2-(4-methylphenyl)-1H-imidazole-5-carboxamide(100 mg, 87%) as a yellow oil. LCMS (ESI) m/z 340 [M+H].

Step 4.3-([4-hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl]methyl)-7-(4-methylphenyl)-3H,4H-imidazo[4,3-f][1,2,4]triazin-4-one(I-119)

A 100-mL round-bottom flask fitted with a magnetic stir bar was chargedwith3-[(4-hydroxypiperidin-4-yl)methyl]-7-(4-methylphenyl)-3H,4H-imidazo[4,3-f][1,2,4]triazin-4-one(100 mg, 0.26 mmol),2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (148 mg, 0.39 mmol), N-ethyldiisopropylamine (132μL, 0.78 mmol), dichloromethane (10 mL), 3-(1H-pyrazol-1-yl)butanoicacid (48 mg, 0.31 mmol). The solution was stirred for 1 h at 0° C. in anice/salt bath. The resulting solution was diluted with water (10 mL).The product was extracted with dichloromethane (3×20 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The crude product was purified by preparativeHPLC* to afford3-([4-hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl]methyl)-7-(4-methylphenyl)-3H,4H-imidazo[4,3-f][1,2,4]triazin-4-oneas a racemic mixture (I-119, 45 mg, 37%). ¹H NMR (400 MHz, DMSO-d₆) δ1.24-1.31 (m, 2H), 1.41 (d, J=5.6 Hz, 3H), 1.52-1.59 (m, 2H), 2.38 (s,3H), 2.66-2.76 (m, 1H), 2.92-3.00 (m, 2H), 3.15-3.25 (m, 1H), 3.60-3.64(m, 1H), 3.82-3.94 (m, 2H), 4.01-4.05 (m, 1H), 4.77-4.80 (m, 1H), 4.98(s, 1H), 6.13-6.15 (m, 1H), 7.35-7.39 (m, 3H), 7.69-7.71 (m, 1H), 7.29(d, J=0.8 Hz, 1H), 8.05-8.06 (m, 1H), 8.20 (s, 1H), 8.23 (s, 1H).*Column: X Bridge, C18, 5 μm, 19×150 mm. Mobile phase A: 0.1% aqueousammonium bicarbonate/Mobile phase B: acetonitrile. Gradient: 9% B to 29%B over 10 min. Detector: 220 and 254 nm.

Chiral separation of compound I-119 was performed on a CHIRAL PAK 1Acolumn, 5 μm, 0.46×25 cm, Mobile phase A: MeOH (1% diethylamine)/Mobilephase B: dichloromethane (9:1). Flow Rate: 1 ml/min. Injection Volume: 5μL. Temp: 25° C., Total Run Time: 20 min, Detector: 254 nm. RT₁=9.98min, RT₂=16.0 min.

First eluting enantiomer:3-([4-Hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl]methyl)-7-(4-methylphenyl)-3H,4H-imidazo[4,3-f][1,2,4]triazin-4-one(I-120): ¹H NMR (400 MHz, DMSO-d₆) δ 1.24-1.62 (m, 7H), 2.75-2.68 (m,1H), 2.38 (s, 3H), 2.63-2.78 (m, 1H), 2.85-2.99 (m, 2H), 3.14-3.25 (m,1H), 3.28-3.64 (m, 1H), 3.84-3.88 (m, 2H), 4.01-4.05 (m, 1H), 4.76-4.82(m, 1H), 4.94 (brs, 1H), 6.13-6.16 (m, 1H), 7.35-7.39 (m, 3H), 7.70 (dd,J=2.4, 3.6 Hz, 1H), 7.93 (d, J=1.2 Hz, 1H), 8.05 (d, J=3.2 Hz, 1H), 8.21(s, 1H), 8.23 (s, 1H). LCMS (ESI) m/z 476.

Second eluting enantiomer:3-([4-Hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl]methyl)-7-(4-methylphenyl)-3H,4H-imidazo[4,3-f][1,2,4]triazin-4-one(I-121): ¹H NMR (400 MHz, DMSO-d₆) δ 1.31-1.66 (m, 7H), 2.38 (s, 3H),2.65-2.75 (m, 1H), 2.85-0.299 (m, 2H), 3.12-3.25 (m, 1H), 3.61-3.64 (m,1H), 3.84-3.88 (m, 2H), 4.01-4.05 (m, 1H), 4.76-4.82 (m, 1H), 4.94 (brs,1H), 6.12-6.17 (m, 1H), 7.35-7.39 (m, 3H), 7.70 (dd, J=2.4, 3.6 Hz, 1H),7.93 (d, J=0.8 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 8.21 (s, 1H), 8.23 (s,1H). LCMS (ESI) m/z 476

The compounds in Table 1 were synthesized according to the generalprocedure above in Method L.

TABLE 1 Method Intermediate and MS Cmpd of Starting Materials (ESI, m/z)No.: synthesis In Synthesis [M + H]⁺ ¹H-NMR δ (ppm) I-122 L 2-12 and 2-479 ¹H NMR (300 MHz, DMSO-d₆) δ cyclopropyloxazole- 0.95-1.01 (m, 2H),1.06-1.12 (m, 5-carboxylic acid 2H), 1.47-1.69 (m, 4H), 2.12-2.19 (m,1H), 3.10-3.47 (m, 2H), 3.93 (s, 2H), 3.94-4.13 (m, 4H), 5.04 (brs, 1H),7.40 (t, J = 9.0 Hz, 2H), 7.49 (s, 1H), 7.94 (s, 1H), 8.09 (s, 1H),8.34- 8.39 (m, 2H). I-123 L 2-12 and 2-13 514 ¹H NMR (300 MHz, DMSO-d₆)δ 1.35-1.75 (m, 4H), 3.13-3.29 (m, 2H), 3.37-3.59 (m, 1H), 3.95 (s, 2H),4.12-4.28 (m, 1H), 5.01 (brs, 1H), 6.57-6.58 (m, 1H), 7.40 (t, J = 9.0Hz, 2H), 7.53 (d, J = 5.4 Hz, 2H), 7.78 (d, J = 1.5 Hz, 1H), 7.91 (d, J= 8.7 Hz, 2H), 7.95 (s, 1H), 7.95 (s, 1H), 8.10 (s, 1H), 8.36 (dd, J =5.4, 9.0 Hz, 2H), 8.56 (d, J = 2.4 Hz, 1H). I-124 L 2-12 and 4- 462 ¹HNMR (400 MHz, DMSO-d₆) δ methylbenzoic acid 1.31-1.67 (m, 4H), 2.32 (s,3H), 3.02- 3.28 (m, 2H), 3.35-3.58 (m, 1H), 3.92 (s, 2H), 4.09-4.23 (m,1H), 4.97 (brs, 1H), 7.20-7.30 (m, 4H), 7.36-7.41 (m, 2H), 7.93 (s, 1H),8.08 (s, 1H), 8.33-8.37 (m, 2H). I-125 L 2-12 and 3-fluoro- 480 ¹H NMR(400 MHz, DMSO-d₆) δ 4-methylbenzoic 1.31-1.69 (m, 4H), 2.24 (s, 3H),3.00- acid 3.28 (m, 2H), 3.33-3.48 (m, 1H), 3.92 (s, 2H), 4.08-4.26 (m,1H), 4.98 (brs, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 10.0 Hz,1H), 7.32-7.41 (m, 3H), 7.93 (s, 1H), 8.07 (s, 1H), 8.37- 8.33 (m, 2H).

Biochemical Assays Example 27: USP7 Assay A (Ubitquin-Rhodamine 110Assay)

Each assay was performed in a final volume of 15 μL in assay buffercontaining 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution;Corning 46-031-CM)), 1 mM GSH (L-Glutathione reduced; Sigma #G4251),0.03% BGG (0.22 μM filtered, Sigma, #G7516-25G), and 0.01% Triton X-100(Sigma, #T9284-10L). Nanoliter quantities of either an 8-point or10-point, 3-fold serial dilution in DMSO was pre-dispensed into assayplates (Perkin Elmer, ProxiPlate-384 F Plus, #6008269) for a final testconcentration range of either 25 M to 11 nM or 25 μM to 1.3 nM,respectively. The final concentration of the enzyme (USP7, constructUSP7 (208-1102) 6*His, Viva Biotech) in the assay was 62.5 μM. Finalsubstrate (Ub-Rh110; Ubiquitin-Rhodamine 110, R&D Systems #U-555)concentration was 25 nM with [Ub-Rh110]<<Km. 5 μL of 2× enzyme was addedto assay plates (pre-stamped with compound) preincubated with USP7 for30 minutes and then 5 μL of 2×Ub-Rh110 was added to assay plates. Plateswere incubated stacked for 20 minutes at room temperature before 5 μL ofstop solution (final concentration of 10 mM citric acid in assay buffer(Sigma, #251275-500G)). Fluorescence was read on the Envision(Excitation at 485 nm and Emission at 535 nm; Perkin Elmer) or on thePheraSTAR (Excitation at 485 nm and Emission at 535 nm; BMG Labtech).

Example 28: USP7 Assay B (Ubitquin-Rhodaminel 10 Assay)

Each assay was performed in a final volume of 20 μL in assay buffercontaining 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution;Corning 46-031-CM)), 2 mM CaCl₂ (1M Calcium Chloride solution; Sigma#21114) 1 mM GSH (L-Glutathione reduced; Sigma #G4251), 0.01% Prionex(0.22 μM filtered, Sigma #G-0411), and 0.01% Triton X-100. Stockcompound solutions were stored at −20° C. as 10 mM in DMSO. Up to 1month prior to the assay, 2 mM test compounds were pre-dispensed intoassay plates (Black, low volume; Corning #3820) and frozen at −20° C.Prestamped assay plates were allowed to come to room temperature on theday of the assay. For the screen, 100 nL of 2 mM was pre-dispensed for afinal screening concentration of 10 μM (DMSO_((fc))=0.5%). For follow-upstudies, 250 nL of an 8-point, 3-fold serial dilution in DMSO waspre-dispensed into assay plates for a final test concentration of 25M-11 nM (1.25% DMSO final concentration). Unless otherwise indicated,all follow-up assays were run on triplecate plates. Enzyme (USP7,construct Met (208-1102)-TEV-6*His; Viva Q93009-1) concentration andincubation times were optimized for the maximal signal-to-backgroundwhile maintaining initial velocity conditions at a fixed substrateconcentration. The final concentration of the enzyme in the assay waseither 75 or 250 μM. Final substrate (Ub-Rh110; Ubiquitin-Rhodamine 110,R&D Systems (biotechne)#U-555) concentration was 25 nM with[Ub-Rh110]<<Km. Pre-stamped with compounds were either not preincubatedor preincubated with USP7 between 30 to 120 minutes prior to theaddition of 10 μL of 2×Ub-Rh110 to compound plates. Plates wereincubated stacked for either 23 or 45 minutes at room temperature beforefluorescence was read on the Envision (Excitation at 485 nm and Emissionat 535 nm; Perkin Elmer) or on the PheraSTAR (Excitation at 485 nm andEmission at 535 nm; BMG Labtech).

Data from USP7 Assays A and B were reported as percent inhibition (inh)compared with control wells based on the following equation: %inh=1−((FLU−Ave_(Low))/(Ave_(High)−Ave_(Low))) where FLU=measuredFluorescence (See Tables 2 and 3). Ave_(Low)=average Fluorescence of noenzyme control (n=16). Ave_(High)=average Fluorescence of DMSO control(n=16). IC₅₀ values were determined by curve fitting of the standard 4parameter logistic fitting algorithm included in the Activity Basesoftware package: IDBS XE Designer Model205. Data is fitted using theLevenburg Marquardt algorithm. IC₅₀ data from USP7 Assays A and B forthe compounds of the invention can be found in Tables 2 and 3.

TABLE 2 USP7 activity of compounds of the invention in USP7 assay A.++++ indicates an IC₅₀ of less than about 0.2 μM, +++ indicates an IC₅₀between about 0.2 μM and about 1 μM, ++ indicates an IC₅₀ between about1 μM and about 10 μM, and + indicates an IC₅₀ greater than 10 μM. USP7Assay A HPLC Method LCMS: retention Cmpd of Intermediate (ESI) m/z time/IC₅₀ No.: synthesis In Synthesis [M + H] mins (μM) I-116 J 2-11 466.261.22 + I-117 K 2-11 462.33 1.26 ++ I-119 L  2-119 476.24 1.09 ++ I-120 L476.23 1.09 ++ I-121 L 476.23 1.09 + I-122 J 2-12, 2-13 479.09 1.12 ++I-123 J 2-12 514.15 1.22 ++ I-124 J 2-12 462.13 1.31 + I-125 J 2-12480.13 1.36 +

TABLE 3 USP7 activity of compounds of the invention in USP7 assay B.++++ indicates an IC₅₀ of less than about 0.2 μM, +++ indicates an IC₅₀between about 0.2 μM and about 1 μM, ++ indicates an IC₅₀ between about1 μM and about 10 μM, and + indicates an IC₅₀ greater than 10 μM. USP7Assay B HPLC Method LCMS: retention Cmpd of Intermediate (ESI) m/z time/IC₅₀ No.: synthesis In Synthesis [M + H] mins (μM) I-1  A — 395.26 1.17+++ I-2  B 2-3 429.17 1.32 + I-3  B 2-3 435.15 1.27 + I-4  B 2-3 447.221.35 + I-5  B 2-4 473.20 1.37 ++ I-6  B 2-4 443.19 1.51 ++ I-7  B 2-4443.21 1.52 ++ I-8  B 2-4 459.21 1.40 ++ I-9  B 2-4 461.21 1.55 + I-10 B 2-4 459.18 1.42 + I-11  B 2-4 429.18 1.42 ++ I-12  B 2-4 463.15 1.56++ I-13  B 2-4 463.15 1.55 ++ I-14  B 2-4 471.24 1.73 + I-15  B 2-4497.20 1.60 + I-16  B 2-4 472.18 0.92 ++ I-17  B 2-4 457.22 1.62 + I-18 B 2-4 454.19 1.29 + I-19  B 2-4 454.19 1.31 + I-20  B 2-4 449.14 1.49 +I-21  B 2-4 480.24 1.11 ++ I-22  B 2-4 469.23 0.79 + I-23  B 2-4 486.191.28 ++ I-24  B 2-4 483.25 1.20 ++ I-25  B 2-4 482.22 1.55 +++ I-26  B2-4 540.33 1.36 + I-27  B 2-4 435.14 1.38 + I-28  B 2-4 435.15 1.36 +I-29  B 2-4 447.19 1.42 ++ I-30  B 2-4 447.18 1.44 ++ I-31  C 2-1 420.171.16 + I-32  C 2-1 420.15 1.17 + I-33  C 2-1 477.23 1.17 + I-34  B 2-5137.03 0.88 + I-35  B 2-5 459.15 1.43 + I-36  B 2-5 429.14 1.44 + I-37 B 2-5 473.20 1.54 + I-38  B 2-5 500.23 1.10 ++ I-39  D 2-1 526.31 1.10++ I-40  B 2-5 489.20 1.41 + I-41  B 2-5 500.22 1.12 + I-42  B 2-5480.17 1.24 ++ I-43  B 2-5 480.20 1.10 ++ I-44  B 2-5 489.20 1.44 +I-45  B 2-5 494.20 0.99 ++ I-46  B 2-5 483.20 0.88 + I-47  B 2-5 470.131.21 + I-48  B 2-5 470.19 0.98 + I-49  A — 429.17 1.47 ++ I-50  D 2-1463.15 1.43 + I-51  D 2-1 560.29 1.16 ++ I-52  B 2-5 540.28 1.22 + I-53 C 2-1 437.23 1.46 ++ I-54  C 2-1 406.20 1.14 + I-55  C 2-1 471.26 1.54++ I-56  C 2-1 395.19 1.18 ++++ I-57  C 2-1 384.19 1.02 ++++ I-58  C 2-1421.24 1.32 + I-59  C 2-1 436.15 1.02 + I-60  C 2-1 409.22 1.25 ++ I-61 C 2-1 493.18 1.15 ++ I-62  C 2-1 461.17 1.45 ++ I-63  C 2-1 395.19 1.17++ I-64  C 2-1 483.25 0.85 ++ I-65  C 2-1 433.20 0.95 ++ I-66  C 2-1449.20 0.83 + I-67  C 2-1 515.24 1.31 ++ I-68  C 2-1 484.21 1.07 ++I-69  C 2-1 461.23 1.06 ++ I-70  C 2-1 449.18 1.33 ++ I-71  C 2-1 457.201.23 ++ I-72  C 2-1 472.24 1.48 ++ I-73  H 2-1 462.26 1.14 + I-74  H 2-1515.18 0.97 + I-75  1 — 484.27 0.73 + I-76  A 2-7 409.14 1.27 +++ I-77 A 2-7 409.15 1.27 ++ I-78  C 2-1 534.17 1.09 + I-79  C 2-1 574.24 1.30++ I-80  C 2-1 445.11 1.35 + I-81  E 2-6 452.14 0.98 +++ I-82  F 2-6467.15 0.95 +++ I-83  A 2-8 415.17 1.49 ++ I-84  A 2-8 409.21 1.23 ++I-85  F 2-6 485.16 1.16 + I-86  F 2-6 465.19 1.09 + I-87  F 2-6 483.181.00 + I-88  F 2-6 469.16 1.02 + I-89  F 2-6 465.21 1.09 + I-90  F 2-6491.24 1.22 + I-91  F 2-6 499.21 1.10 + I-92  F 2-6 479.24 1.07 + I-93 F 2-6 487.21 1.16 + I-94  F 2-6 483.24 0.99 + I-95  F 2-6 479.24 0.93 +I-96  F 2-6 469.21 1.07 + I-97  F 2-6 483.24 1.09 + I-98  F 2-6 479.221.09 + I-99  F 2-6 479.25 1.12 + I-100 F 2-6 476.20 0.98 + I-101 F 2-6481.19 1.00 + I-102 E 2-6 504.16 1.24 + I-103 E 2-6 518.11 1.16 + I-104E 2-6 550.22 1.32 + I-105 E 2-6 534.11 1.32 + I-106 E 2-6 534.11 1.29 ++I-107 E 2-6 464.18 1.18 ++ I-108 E 2-6 484.13 1.25 + I-109 E 2-6 464.181.14 + I-110 E 2-6 520.16 1.13 + I-111 E 2-6 504.10 1.17 + I-112 E 2-6519.18 1.30 ++ I-113 E 2-6 512.20 1.26 + I-114 G 2-2 512.34 1.14 ++I-115 A 2-9 430.29 1.18 ++

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1-47. (canceled)
 48. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X₁ is C; X₂ isCR₇ or N; R₁ is —OH; R₂ is (C₁—C) alkyl, (C₆-C₁₄) aryl, cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₈; R₄ is(C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the aryl is optionallysubstituted with one or more R₂₂; R₅ and R_(5′) are independently H; R₆is H; R₇ is H; each R₈ is independently (C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl,—(C₀-C₄)-alkylene-O-heteroaryl, halogen, —C(O)R₁₂, wherein alkyl,alkylene, aryl, and heteroaryl are optionally substituted with one ormore R₉; each R₉ is independently at each occurrence (C₁-C₆) alkyl,halogen, or —NR₁₄S(O)_(q)R₁₅; each R₁₂ is independently (C₂-C₆) alkenyl;each R₁₄ and R₁₅ is independently H or (C₂-C₆) alkenyl; each R₂₂ isindependently at each occurrence (C₆-C₁₄) aryl, —O—(C₃-C₈)cycloalkyl,halogen, wherein aryl and cycloalkyl are optionally substituted with oneor more substituents independently selected from halogen; m is 0; n is1; and q is
 2. 49. The compound of claim 48, wherein R₄ is (C₆-C₁₄)aryl, optionally substituted with one or more R₂₂.
 50. The compound ofclaim 49, wherein R₂₂ is (C₆-C₁₄) aryl.
 51. The compound of claim 50,wherein R₂ is heterocycloalkyl, optionally substituted with one or moreR₈.
 52. The compound of claim 51, wherein R₈ is —C(O)R₁₂ and R₁₂ is(C₂-C₆) alkenyl.
 53. The compound of claim 49, wherein R₂₂ is halogen.54. The compound of claim 53, wherein R₂ is (C₁-C₈) alkyl, optionallysubstituted with one or more R₈.
 55. The compound of claim 54, whereinR₈ is independently selected from heteroaryl and halogen, whereinheteroaryl is substituted with one or more R₉, and wherein R₉ ishalogen.
 56. The compound of claim 53, wherein R₂ is cycloalkyl,optionally substituted with one or more R₈.
 57. The compound of claim56, wherein R₈ is O-heteroaryl, wherein heteroaryl is substituted withone or more R₉, and wherein R₉ is (C₁-C₆) alkyl.
 58. The compound ofclaim 49, wherein R₂₂ is —O—(C₃-C₈)cycloalkyl, optionally substitutedwith one or more substituents independently selected from halogen. 59.The compound of claim 58, wherein R₂ is cycloalkyl, optionallysubstituted with one or more R₈.
 60. The compound of claim 59, whereinR₈ is (C₁-C₆) alkyl.
 61. The compound of claim 48, wherein R₄ is (C₁-C₆)alkyl.
 62. The compound of claim 61, wherein R₂ is aryl, optionallysubstituted with one or more R₈.
 63. The compound of claim 62, wherein:R₈ is aryl, optionally substituted with one or more R₉; R₉ is—NR₁₄S(O)_(q)R₁₅; R₁₄ is H; and R₁₅ is (C₂-C₆) alkenyl.
 64. Apharmaceutical composition comprising a compound of claim 48, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.